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  • Articles  (165,862)
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  • 1
    Electronic Resource
    Electronic Resource
    ROLE OF FXYD PROTEINS IN ION TRANSPORT (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 431-459 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The FXYD proteins are a family of seven homologous single transmembrane segment proteins (FXYD1Đ??7), expressed in a tissue-specific fashion. The FXYD proteins modulate the function of Na,K-ATPase, thus adapting kinetic properties of active Na+ and K+ transport to the specific needs of different cells. Six FXYD proteins ( 1Đ??5, 7 ) are known to interact with Na,K-ATPase and affect its kinetic properties in specific ways. Although effects of FXYD proteins on parameters such as K1/2Na+, K1/2K+, KmATP, and Vmax are modest, usually twofold, these effects may have important long-term consequences for homeostasis of cation balance. In this review we summarize basic features of FXYD proteins and present recent evidence for functional effects, structure-function relations and structural interactions with Na,K-ATPase. We then discuss possible physiological roles, based on in vitro observations and newly available knockout mice models. Finally, we also consider evidence that FXYD proteins affect functioning of other ion transport systems.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.131852
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  • 2
    Electronic Resource
    Electronic Resource
    ENDOTHELIAL-CARDIOMYOCYTE INTERACTIONS IN CARDIAC DEVELOPMENT AND REPAIR (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 51-66 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Communication between endothelial cells and cardiomyocytes regulates not only early cardiac development but also adult cardiomyocyte function, including the contractile state. In the normal mammalian myocardium, each cardiomyocyte is surrounded by an intricate network of capillaries and is next to endothelial cells. Cardiomyocytes depend on endothelial cells not only for oxygenated blood supply but also for local protective signals that promote cardiomyocyte organization and survival. While endothelial cells direct cardiomyocytes, cardiomyocytes reciprocally secrete factors that impact endothelial cell function. Understanding how endothelial cells communicate with cardiomyocytes will be critical for cardiac regeneration, in which the ultimate goal is not simply to improve systolic function transiently but to establish new myocardium that is both structurally and functionally normal in the long term.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.124629
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  • 3
    Electronic Resource
    Electronic Resource
    PERMEATION AND SELECTIVITY OF TRP CHANNELS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 685-717 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Ion channels are pore-forming transmembrane proteins that allow ions to permeate biological membranes. Pore structure plays a crucial role in determining the ion permeation and selectivity properties of particular channels. In the past few decades, efforts have been undertaken to identify key elements of the pore regions of different classes of ion channels. In this review, we summarize current knowledge about permeation and selectivity of channel proteins from the transient receptor potential (TRP) superfamily. Whereas all TRP channels are permeable for cations, only two TRP channels are impermeable for Ca2+ (TRPM4, TRPM5), and two others are highly Ca2+ permeable (TRPV5, TRPV6). Despite the great advances in the TRP channel field during the past decade, only a limited number of reports have dealt with functional characterization of pore properties, biophysical aspects of cation permeation, or description of pore structures of TRP channels. This review gives an overview of available experimental and theoretical data and discusses the functional impact of pore-structure modifications on TRP channel properties.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040204.101406
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  • 4
    Electronic Resource
    Electronic Resource
    PROTECTING THE PUMP: Controlling Myocardial Inflammatory Responses (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 67-95 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Because of the anatomy, function, and nonregenerative nature of the myocardium, inflammation in this tissue is not well tolerated. Nevertheless, various diseases of the heart are characterized by inflammatory responses involving the effector mechanisms of innate and adaptive (lymphocyte-dependent) immunity. The innate immune response to ischemia-reperfusion injury is, by far, the most common cause of myocardial inflammation. Innate responses may have beneficial influences that preserve myocardial function in the short term but may be maladaptive in chronic states. Adaptive responses in the myocardium occur with infection or loss of tolerance, and lead to myocarditis. Given the narrow margin for benefit of cardiac inflammation, special regulatory mechanisms likely raise the threshold, compared to other tissues, for the induction and persistence of adaptive immune responses. These mechanisms include strong central and peripheral T cell tolerance to heart antigens and induction of anti-inflammatory feedback mechanisms involving cytokines such as interferon-??.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.124611
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  • 5
    Electronic Resource
    Electronic Resource
    LXRS AND FXR: The Yin and Yang of Cholesterol and Fat Metabolism (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 159-191 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Liver X receptors (LXRs) and farnesoid X receptor (FXR) are nuclear receptors that function as intracellular sensors for sterols and bile acids, respectively. In response to their ligands, these receptors induce transcriptional responses that maintain a balanced, finely tuned regulation of cholesterol and bile acid metabolism. LXRs also permit the efficient storage of carbohydrate- and fat-derived energy, whereas FXR activation results in an overall decrease in triglyceride levels and modulation of glucose metabolism. The elegant, dual interplay between these two receptor systems suggests that they coevolved to constitute a highly sensitive and efficient system for the maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that the tissue-specific action of these receptors is also crucial for the proper function of the cardiovascular, immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXR represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.033104.152158
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  • 6
    Electronic Resource
    Electronic Resource
    BRAINSTEM CIRCUITS REGULATING GASTRIC FUNCTION (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 279-305 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Brainstem parasympathetic circuits that modulate digestive functions of the stomach are comprised of afferent vagal fibers, neurons of the nucleus tractus solitarius (NTS), and the efferent fibers originating in the dorsal motor nucleus of the vagus (DMV). A large body of evidence has shown that neuronal communications between the NTS and the DMV are plastic and are regulated by the presence of a variety of neurotransmitters and circulating hormones as well as the presence, or absence, of afferent input to the NTS. These data suggest that descending central nervous system inputs as well as hormonal and afferent feedback resulting from the digestive process can powerfully regulate vago-vagal reflex sensitivity. This paper first reviews the essential "static" organization and function of vago-vagal gastric control neurocircuitry. We then present data on the opioidergic modulation of NTS connections with the DMV as an example of the "gating" of these reflexes, i.e., how neurotransmitters, hormones, and vagal afferent traffic can make an otherwise static autonomic reflex highly plastic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040504.094635
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  • 7
    Electronic Resource
    Electronic Resource
    SGK KINASES AND THEIR ROLE IN EPITHELIAL TRANSPORT (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 461-490 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The serum/glucocorticoid-induced kinase Sgk1 plays an important role in the regulation of epithelial ion transport. This kinase is very rapidly regulated at the transcriptional level as well as via posttranslational modifications involving phosphorylation by the MAP or PI-3 kinase pathways and/or ubiquitylation. Although Sgk1 is a cell survival kinase, its primary role likely concerns the regulation of epithelial ion transport, as suggested by the phenotype of Sgk1-null mice, which display a defect in Na+ homeostasis owing to disturbed renal tubular Na+ handling. In this review we first discuss the molecular, cellular, and regulatory aspects of Sgk1 and its paralogs. We then discuss its roles in the physiology and pathophysiology of epithelial ion transport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.131654
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  • 8
    Electronic Resource
    Electronic Resource
    DESIGN AND FUNCTION OF SUPERFAST MUSCLES: New Insights into the Physiology of Skeletal Muscle (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 193-221 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Superfast muscles of vertebrates power sound production. The fastest, the swimbladder muscle of toadfish, generates mechanical power at frequencies in excess of 200 Hz. To operate at these frequencies, the speed of relaxation has had to increase approximately 50-fold. This increase is accomplished by modifications of three kinetic traits: (a) a fast calcium transient due to extremely high concentration of sarcoplasmic reticulum (SR)-Ca2+ pumps and parvalbumin, (b) fast off-rate of Ca2+ from troponin C due to an alteration in troponin, and (c) fast cross-bridge detachment rate constant (g, 50 times faster than that in rabbit fast-twitch muscle) due to an alteration in myosin. Although these three modifications permit swimbladder muscle to generate mechanical work at high frequencies (where locomotor muscles cannot), it comes with a cost: The high g causes a large reduction in attached force-generating cross-bridges, making the swimbladder incapable of powering low-frequency locomotory movements. Hence the locomotory and sound-producing muscles have mutually exclusive designs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.105418
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  • 9
    Electronic Resource
    Electronic Resource
    CLAUDINS AND EPITHELIAL PARACELLULAR TRANSPORT (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 403-429 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Tight junctions form continuous intercellular contacts controlling solute movement through the paracellular pathway across epithelia. Paracellular barriers vary among epithelia in electrical resistance and behave as if they are lined with pores that have charge and size selectivity. Recent evidence shows that claudins, a large family (at least 24 members) of intercellular adhesion molecules, form the seal and its variable pore-like properties. This evidence comes from the study of claudins expressed in cultured epithelial cell models, genetically altered mice, and human mutants. We review information on the structure, function, and transcriptional and posttranslational regulation of the claudin family as well as of their evolutionarily distant relatives called the PMP22/EMP/MP20/claudin, or pfam00822, superfamily.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.131404
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  • 10
    Electronic Resource
    Electronic Resource
    THE COMPARATIVE PHYSIOLOGY OF FOOD DEPRIVATION: From Feast to Famine (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 223-251 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The ability of animals to survive food deprivation is clearly of considerable survival value. Unsurprisingly, therefore, all animals exhibit adaptive biochemical and physiological responses to the lack of food. Many animals inhabit environments in which food availability fluctuates or encounters with appropriate food items are rare and unpredictable; these species offer interesting opportunities to study physiological adaptations to fasting and starvation. When deprived of food, animals employ various behavioral, physiological, and structural responses to reduce metabolism, which prolongs the period in which energy reserves can cover metabolism. Such behavioral responses can include a reduction in spontaneous activity and a lowering in body temperature, although in later stages of food deprivation in which starvation commences, activity may increase as food-searching is activated. In most animals, the gastrointestinal tract undergoes marked atrophy when digestive processes are curtailed; this structural response and others seem particularly pronounced in species that normally feed at intermittent intervals. Such animals, however, must be able to restore digestive functions soon after feeding, and these transitions appear to occur at low metabolic costs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.105739
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  • 11
    Electronic Resource
    Electronic Resource
    REGULATION OF NORMAL AND CYSTIC FIBROSIS AIRWAY SURFACE LIQUID VOLUME BY PHASIC SHEAR STRESS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 543-561 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The physical removal of viruses and bacteria on the mucociliary escalator is an important aspect of the mammalian lung's innate defense mechanism. The volume of airway surface liquid (ASL) present in the respiratory tract is a critical determinant of both mucus hydration and the rate of mucus clearance from the lung. ASL volume is maintained by the predominantly ciliated epithelium via coordinated regulation of (a) absorption, by the epithelial Na+ channel, and (b) secretion, by the Ca2+ -activated Cl channel (CaCC) and CFTR. This review provides an update on our current understanding of how shear stress regulates ASL volume height in normal and cystic fibrosis (CF) airway epithelia through extracellular ATP- and adenosine (ADO)-mediated pathways that modulate ion transport and ASL volume homeostasis. We also discuss (a) how derangement of the ADO-CFTR pathway renders CF airways vulnerable to viral infections that deplete ASL volume and produce mucus stasis, and (b) potential shear stressĐ??dependent therapies for CF.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.072304.112754
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  • 12
    Electronic Resource
    Electronic Resource
    TRP CHANNELS IN C. ELEGANS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 719-736 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The TRP (transient receptor potential) superfamily of cation channels is present in all eukaryotes, from yeast to mammals. Many TRP channels have been studied in the nematode Caenorhabditis elegans, revealing novel biological functions, regulatory modes, and mechanisms of localization. C. elegans TRPV channels function in olfaction, mechanosensation, osmosensation, and activity-dependent gene regulation. Their activity is regulated by G protein signaling and polyunsaturated fatty acids. C. elegans TRPPs related to human polycystic kidney disease genes are expressed in male-specific neurons. The KLP-6 kinesin directs TRPP channels to cilia, where they may interact with F0/F1 ATPases. A sperm-specific TRPC channel, TRP-3, is required for fertilization. Upon sperm activation, TRP-3 translocates from an intracellular compartment to the plasma membrane to allow store-operated Ca2+ entry. The TRPM channels GON-2 and GTL-2 regulate Mg2+ homeostasis and Mg2+ uptake by intestinal cells; GON-2 is also required for gonad development. The TRPML CUP-5 promotes normal lysosome biogenesis and prevents apoptosis. Dynamic, precise expression of TRP proteins generates a remarkable range of cellular functions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040204.100715
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  • 13
    Electronic Resource
    Electronic Resource
    INSIGHTS ON TRP CHANNELS FROM IN VIVO STUDIES IN DROSOPHILA (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 649-684 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Transient receptor potential (TRP) channels mediate responses in a large variety of signaling mechanisms. Most studies on mammalian TRP channels rely on heterologous expression, but their relevance to in vivo tissues is not entirely clear. In contrast, Drosophila TRP and TRP-like (TRPL) channels allow direct analyses of in vivo function. In Drosophila photoreceptors, activation of TRP and TRPL is mediated via the phosphoinositide cascade, with both Ca2+ and diacylglycerol (DAG) essential for generating the light response. In tissue culture cells, TRPL channels are constitutively active, and lipid second messengers greatly facilitate this activity. Inhibition of phospholipase C (PLC) completely blocks lipid activation of TRPL, suggesting that lipid activation is mediated via PLC. In vivo studies in mutant Drosophila also reveal an acute requirement for lipid-producing enzyme, which may regulate PLC activity. Thus, PLC and its downstream second messengers, Ca2+ and DAG, constitute critical mediators of TRP/TRPL gating in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040204.100939
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  • 14
    Electronic Resource
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    CARDIAC REGENERATION: Repopulating the Heart (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 29-49 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Many forms of pediatric and adult heart disease result from a deficiency in cardiomyocyte number. Through repopulation of the heart with new cardiomyocytes (that is, induction of regenerative cardiac growth), cardiac disease potentially can be reversed, provided that the newly formed myocytes structurally and functionally integrate in the preexisting myocardium. A number of approaches have been utilized to effect regenerative growth of the myocardium in experimental animals. These include interventions aimed at enhancing the ability of cardiomyocytes to proliferate in response to cardiac injury, as well as transplantation of cardiomyocytes or myogenic stem cells into diseased hearts. Here we review efforts to induce myocardial regeneration. We also provide a critical review of techniques currently used to assess cardiac regeneration and functional integration of de novo cardiomyocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.124530
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  • 15
    Electronic Resource
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    FROM MICE TO MEN: Insights into the Insulin Resistance Syndromes (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 123-158 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The insulin resistance syndrome refers to a constellation of findings, including glucose intolerance, obesity, dyslipidemia, and hypertension, that promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. Defining the pathophysiological links between insulin resistance, the insulin resistance syndrome, and its sequelae is critical to understanding and treating these disorders. Over the past decade, two approaches have provided important insights into how changes in insulin signaling produce the spectrum of phenotypes associated with insulin resistance. First, studies using tissue-specific knockouts or tissue-specific reconstitution of the insulin receptor in vivo in mice have enabled us to deconstruct the insulin resistance syndromes by dissecting the contributions of different tissues to the insulin-resistant state. Second, in vivo and in vitro studies of the complex network of insulin signaling have provided insight into how insulin resistance can develop in some pathways whereas insulin sensitivity is maintained in others. These data, taken together, give us a framework for understanding the relationship between insulin resistance and the insulin resistance syndromes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.124723
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  • 16
    Electronic Resource
    Electronic Resource
    INTERSTITIAL CELLS OF CAJAL AS PACEMAKERS IN THE GASTROINTESTINAL TRACT (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 307-343 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: In the gastrointestinal tract, phasic contractions are caused by electrical activity termed slow waves. Slow waves are generated and actively propagated by interstitial cells of Cajal (ICC). The initiation of pacemaker activity in the ICC is caused by release of Ca2+ from inositol 1,4,5-trisphosphate (IP3) receptorĐ??operated stores, uptake of Ca2+ into mitochondria, and the development of unitary currents. Summation of unitary currents causes depolarization and activation of a dihydropyridine-resistant Ca2+ conductance that entrains pacemaker activity in a network of ICC, resulting in the active propagation of slow waves. Slow wave frequency is regulated by a variety of physiological agonists and conditions, and shifts in pacemaker dominance can occur in response to both neural and nonneural inputs. Loss of ICC in many human motility disorders suggests exciting new hypotheses for the etiology of these disorders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040504.094718
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  • 17
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    AN INTRODUCTION TO TRP CHANNELS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 619-647 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The aim of this review is to provide a basic framework for understanding the function of mammalian transient receptor potential (TRP) channels, particularly as they have been elucidated in heterologous expression systems. Mammalian TRP channel proteins form six-transmembrane (6-TM) cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Selected functional properties of TRP channels from each subfamily are summarized in this review. Although a single defining characteristic of TRP channel function has not yet emerged, TRP channels may be generally described as calcium-permeable cation channels with polymodal activation properties. By integrating multiple concomitant stimuli and coupling their activity to downstream cellular signal amplification via calcium permeation and membrane depolarization, TRP channels appear well adapted to function in cellular sensation. Our review of recent literature implicating TRP channels in neuronal growth cone steering suggests that TRPs may function more widely in cellular guidance and chemotaxis. The TRP channel gene family and its nomenclature, the encoded proteins and alternatively spliced variants, and the rapidly expanding pharmacology of TRP channels are summarized in online supplemental material.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040204.100431
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  • 18
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    COMMENTARY ON THE PLEASURES OF SOLVING IMPOSSIBLE PROBLEMS OF EXPERIMENTAL PHYSIOLOGY (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 1-28 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This commentary presents a series of examples of "impossible experimental problems" that we have encountered over the years in addressing various challenging questions in physiology. We aim to show how stimulating the challenges of physiology can be and demonstrate how our naive invocation of methods from disparate fields of science and engineering has led to delightful resolutions of physiological challenges that were utterly new to this intrepid interdisciplinary researcher.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040504.151957
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  • 19
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    NUCLEAR AND MITOCHONDRIAL COMPARTMENTATION OF OXIDATIVE STRESS AND REDOX SIGNALING (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 215-234 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: New methods to measure thiol oxidation show that redox compartmentation functions as a mechanism for specificity in redox signaling and oxidative stress. Redox Western analysis and redox-sensitive green fluorescent proteins provide means to quantify thiol/disulfide redox changes in specific subcellular compartments. Analyses using these techniques show that the relative redox states from most reducing to most oxidizing are mitochondria 〉 nuclei 〉 cytoplasm 〉 endoplasmic reticulum 〉 extracellular space. Mitochondrial thiols are an important target of oxidant-induced apoptosis and necrosis and are especially vulnerable to oxidation because of the relatively alkaline pH. Maintenance of a relatively reduced nuclear redox state is critical for transcription factor binding in transcriptional activation in response to oxidative stress. The new methods are applicable to a broad range of experimental systems and their use will provide improved understanding of the pharmacologic and toxicologic actions of drugs and toxicants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141122
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  • 20
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    HUMAN FLAVIN-CONTAINING MONOOXYGENASES (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 65-100 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review summarizes recent information concerning the pharmacological and toxicological significance of the human flavin-containing monooxygenase (FMO, EC 1.14.13.8). The human FMO oxygenates nucleophilic heteroatom-containing chemicals and drugs and generally converts them into harmless, polar, readily excreted metabolites. Sometimes, however, FMO bioactivates chemicals into reactive materials that can cause toxicity. Most of the interindividual differences of FMO are due to genetic variability and allelic variation, and splicing variants may contribute to interindividual and interethnic variability observed for FMO-mediated metabolism. In contrast to cytochrome P450 (CYP), FMO is not easily induced nor readily inhibited, and potential adverse drug-drug interactions are minimized for drugs prominently metabolized by FMO. These properties may provide advantages in drug design and discovery, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may be forthcoming. Although exhaustive examples are not available, physiological factors can influence FMO function, and this may have implications for the clinical significance of FMO and a role in human disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141043
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  • 21
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    PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS: How Their Effects on Macrophages Can Lead to the Development of a New Drug Therapy Against Atherosclerosis (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 1-39 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Peroxisome proliferator-activated receptors (PPARs) alpha (ʼ̛), beta/delta (?‚/??), and gamma (??) are members of the nuclear receptor superfamily, which also includes the estrogen, androgen, and glucocorticoid receptors. Recent evidence suggests that PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation in various tissues; however, the mechanisms involved are not completely understood. Anti-diabetic drugs, called glitazones, can selectively activate PPAR??, and hypolipidemic drugs, called fibrates, can weakly activate PPARʼ̛. Both classes of drugs can decrease insulin resistance and dyslipidemias, which also makes them attractive for treating the metabolic syndrome. The metabolic syndrome exhibits a constellation of risk factors for atherosclerosis that include obesity, insulin resistance, dyslipidemias, and hypertension. Interestingly, all three PPARs are present in macrophages and can therefore have a profound effect on several disease processes, including atherosclerosis. Macrophages are key players in atherosclerotic lesion development. Currently, the first line of defense in reducing the risk of atherosclerosis is aimed at lowering low-density lipoproteins (LDL) and raising high-density lipoproteins (HDL), but a large percentage of patients on statins still succumb to coronary artery disease. However, with the development of drugs selectively activating PPARs, a new arsenal of drugs specifically targeting to the macrophage/foam cell may potentially have a profound impact on how we treat cardiovascular disease.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141247
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    THE REGULATION AND PHARMACOLOGY OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 235-276 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Nitric oxide (NO) is a small, diffusible, lipophilic free radical gas that mediates significant and diverse signaling functions in nearly every organ system in the body. The endothelial isoform of nitric oxide synthase (eNOS) is a key source of NO found in the cardiovascular system. This review summarizes the pharmacology of NO and the cellular regulation of endothelial NOS (eNOS). The molecular intricacies of the chemistry of NO and the enzymology of NOSs are discussed, followed by a review of the biological activities of NO. This information is then used to develop a more global picture of the pharmacological control of NO synthesis by NOSs in both physiologic conditions and pathophysiologic states.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121844
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    CYTOCHROME P450 AND XENOBIOTIC RECEPTOR HUMANIZED MICE * (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 41-64 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Most xenobiotics that enter the body are subjected to metabolism that functions primarily to facilitate their elimination. Metabolism of certain xenobiotics can also result in the production of electrophilic derivatives that can cause cell toxicity and transformation. Many xenobiotics can also activate receptors that in turn induce the expression of genes encoding xenobiotic-metabolizing enzymes and xenobiotic transporters. However, there are marked species differences in the way mammals respond to xenobiotics, which are due in large part to molecular differences in receptors and xenobiotic-metabolizing enzymes. This presents a problem in extrapolating data obtained with rodent model systems to humans. There are also polymorphisms in xenobiotic-metabolizing enzymes that can impact drug therapy and cancer susceptibility. In an effort to generate more reliable in vivo systems to study and predict human response to xenobiotics, humanized mice are under development.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100007
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    CHRONIC EFFECTS OF MECHANICAL FORCE ON AIRWAYS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 563-583 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Airways are embedded in the mechanically dynamic environment of the lung. In utero, this mechanical environment is defined largely by fluid secretion into the developing airway lumen. Clinical, whole lung, and cellular studies demonstrate pivotal roles for mechanical distention in airway morphogenesis and cellular behavior during lung development. In the adult lung, the mechanical environment is defined by a dynamic balance of surface, tissue, and muscle forces. Diseases of the airways modulate both the mechanical stresses to which the airways are exposed as well as the structure and mechanical behavior of the airways. For instance, in asthma, activation of airway smooth muscle abruptly changes the airway size and stress state within the airway wall; asthma also results in profound remodeling of the airway wall. Data now demonstrate that airway epithelial cells, smooth muscle cells, and fibroblasts respond to their mechanical environment. A prominent role has been identified for the epithelium in transducing mechanical stresses, and in both the fetal and mature airways, epithelial cells interact with mesenchymal cells to coordinate remodeling of tissue architecture in response to the mechanical environment.
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    THE ASSOCIATION OF NHERF ADAPTOR PROTEINS WITH G PROTEINĐ??COUPLED RECEPTORS AND RECEPTOR TYROSINE KINASES * (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 491-505 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The sodium-hydrogen exchanger regulatory factors (NHERF-1 and NHERF-2) are a family of adaptor proteins characterized by the presence of two tandem PDZ protein interaction domains and a C-terminal domain that binds the cytoskeleton proteins ezrin, radixin, moesin, and merlin. The NHERF proteins are highly expressed in the kidney, small intestine, and other organs, where they associate with a number of transporters and ion channels, signaling proteins, and transcription factors. Recent evidence has revealed important associations between the NHERF proteins and several G proteinĐ??coupled receptors such as the ?‚2-adrenergic receptor, the ?”-opioid receptor, and the parathyroid hormone receptor, as well as growth factor tyrosine kinase receptors such as the platelet-derived growth factor receptor and the epidermal growth factor receptor. This review summarizes the emerging data on the biochemical mechanisms, physiologic outcomes, and potential clinical implications of the assembly and disassembly of receptor/NHERF complexes.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.131050
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    CNG AND HCN CHANNELS: Two Peas, One Pod (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 375-401 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Cyclic nucleotideĐ??activated ion channels play a fundamental role in a variety of physiological processes. By opening in response to intracellular cyclic nucleotides, they translate changes in concentrations of signaling molecules to changes in membrane potential. These channels belong to two families: the cyclic nucleotideĐ??gated (CNG) channels and the hyperpolarization-activated cyclic nucleotideĐ??modulated (HCN) channels. The two families exhibit high sequence similarity and belong to the superfamily of voltage-gated potassium channels. Whereas HCN channels are activated by voltage and CNG channels are virtually voltage independent, both channels are activated by cyclic nucleotide binding. Furthermore, the channels are thought to have similar channel structures, leading to similar mechanisms of activation by cyclic nucleotides. However, although these channels are structurally and behaviorally similar, they have evolved to perform distinct physiological functions. This review describes the physiological roles and biophysical behavior of CNG and HCN channels. We focus on how similarities in structure and activation mechanisms result in common biophysical models, allowing CNG and HCN channels to be viewed as a single genre.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.68.040104.134728
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    OXIDATIVE STRESS IN MARINE ENVIRONMENTS: Biochemistry and Physiological Ecology (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 253-278 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Oxidative stressĐ??the production and accumulation of reduced oxygen intermediates such as superoxide radicals, singlet oxygen, hydrogen peroxide, and hydroxyl radicalsĐ??can damage lipids, proteins, and DNA. Many disease processes of clinical interest and the aging process involve oxidative stress in their underlying etiology. The production of reactive oxygen species is also prevalent in the world's oceans, and oxidative stress is an important component of the stress response in marine organisms exposed to a variety of insults as a result of changes in environmental conditions such as thermal stress, exposure to ultraviolet radiation, or exposure to pollution. As in the clinical setting, reactive oxygen species are also important signal transduction molecules and mediators of damage in cellular processes, such as apoptosis and cell necrosis, for marine organisms. This review brings together the voluminous literature on the biochemistry and physiology of oxidative stress from the clinical and plant physiology disciplines with the fast-increasing interest in oxidative stress in marine environments.
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    THE CONTRIBUTION OF BIOPHYSICAL LUNG INJURY TO THE DEVELOPMENT OF BIOTRAUMA (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 585-618 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Patients with severe acute respiratory distress syndrome who die usually succumb to multiorgan failure as opposed to hypoxia. Despite appropriate resuscitation, some patients' symptoms persist on a downward spiral, apparently propagated by an uncontained systemic inflammatory response. This phenomenon is not well understood. However, a novel hypothesis to explain this observation proposes that it is related to the life-saving ventilatory support used to treat the respiratory failure. According to this hypothesis, mechanical ventilation per se, by alterating both the magnitude and the pattern of lung stretch, can cause changes in gene expression and/or cellular metabolism that ultimately can lead to the development of an overwhelming inflammatory responseĐ??even in the absence of overt structural damage. This mechanism of injury has been termed biotrauma. In this review we explore the biotrauma hypothesis, the causal relationship between biophysical injury and organ failure, and its implications for the future therapy and management of critically ill patients.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.68.072304.113443
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    SIGNALING FOR CONTRACTION AND RELAXATION IN SMOOTH MUSCLE OF THE GUT (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 345-374 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC20) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+]i transient is rapidly dissipated and MLCK inactivated, whereas MLC20 and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC20 phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by Gq/13-coupled receptors are initiated by sequential activation of Gʼ̛q/ʼ̛13, RhoGEF, and RhoA, and involve Rho kinaseĐ??mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC20 phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by Gi-coupled receptors involve sequential activation of G?‚??i, PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC20 directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC2 and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit (a) initial contraction by inhibiting Ca2+ mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC20 dephosphorylation and muscle relaxation.
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    TRANSCRIPTION FACTORS AND CONGENITAL HEART DEFECTS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 97-121 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although there have been important advances in diagnostic modalities and therapeutic strategies for congenital heart defects (CHD), these malformations still lead to significant morbidity and mortality in the human population. Over the past 10 years, characterization of the genetic causes of CHD has begun to elucidate some of the molecular causes of these defects. Linkage analysis and candidate-gene approaches have been used to identify gene mutations that are associated with both familial and sporadic cases of CHD. Complementation of the human studies with developmental studies in mouse models provides information for the roles of these genes in normal development as well as indications for disease pathogenesis. Biochemical analysis of these gene mutations has provided further insight into the molecular effects of these genetic mutations. Here we review genetic, developmental, and biochemical studies of six cardiac transcription factors that have been identified as genetic causes for CHD in humans.
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    STRESS TRANSMISSION IN THE LUNG: Pathways from Organ to Molecule (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 507-541 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Gas exchange, the primary function of the lung, can come about only with the application of physical forces on the macroscale and their transmission to the scale of small airway, small blood vessel, and alveolus, where they serve to distend and stabilize structures that would otherwise collapse. The pathway for force transmission then continues down to the level of cell, nucleus, and molecule; moreover, to lesser or greater degrees most cell types that are resident in the lung have the ability to generate contractile forces. At these smallest scales, physical forces serve to distend the cytoskeleton, drive cytoskeletal remodeling, expose cryptic binding domains, and ultimately modulate reaction rates and gene expression. Importantly, evidence has now accumulated suggesting that multiscale phenomena span these scales and govern integrative lung behavior.
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    CO AS A CELLULAR SIGNALING MOLECULE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 411-449 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Many biological functions of heme oxygenase (HO), such as cytoprotection against oxidative stress, vasodilation, neurotransmission in the central or peripheral nervous systems, and anti-inflammatory, anti-apoptotic, or anti-proliferative potential, have been attributed to its enzymatic byproduct carbon monoxide (CO), although roles for biliverdin/bilirubin and iron have also been proposed. In addition to these well-characterized effects, recent findings reveal that HO-derived CO may act as an oxygen sensor and circadian modulator of heme biosynthesis. In lymphocytes, CO may participate in regulatory T cell function. A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases (MAPK). Furthermore, modulation of caveolin-1 status may serve as an essential component of certain aspects of CO action, such as growth control. In this review, we summarize recent findings of the beneficial or detrimental effects of endogenous CO with an emphasis on the signaling pathways and downstream targets that trigger the action of this gas.
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    REGULATION OF PHOSPHOLIPASE C ISOZYMES BY RAS SUPERFAMILY GTPASES (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 355-379 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The physiological effects of many extracellular stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid-signaling pathways. These signaling responses include the classically described conversion of PtdIns(4,5)P2 to the Ca2+-mobilizing second messenger Ins(1,4,5)P3 and the protein kinase CĐ??activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. Here we discuss how the family of PLCs elaborates a minimal catalytic core typified by PLC-?? to confer multiple modes of regulation on their phospholipase activities. Although PLC-dependent signaling is prominently regulated by direct interactions with heterotrimeric G proteins or tyrosine kinases, the existence of at least 13 divergent PLC isozymes promises a diverse repertoire of regulatory mechanisms for this class of important signaling proteins. We focus here on the recently realized and extensive regulation of inositol lipid signaling by Ras superfamily GTPases directly acting on PLC isozymes and conclude by considering the biological and pharmacological ramifications of this regulation.
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    REGULATION OF DRUG-METABOLIZING ENZYMES AND TRANSPORTERS IN INFLAMMATION (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 123-149 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Inflammation and infection have long been known to downregulate the activity and expression of cytochrome P450 (CYP) enzymes involved in hepatic drug clearance. This can result in elevated plasma drug levels and increased adverse effects. Recent information on regulation of human CYP enzymes is presented, as are new developments in our understanding of the mechanisms of regulation. Experiments to study the effects of modulating CYP activities on the inflammatory response have yielded possible insights into the physiological consequences, if not the purpose, of the downregulation. Regulation of hepatic flavin monooxygenases, UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, as well as of hepatic transporters during the inflammatory response, exhibits similarities and differences with regulation of CYPs.
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    PHARMACOGENOMICS OF ACUTE LEUKEMIA (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 317-353 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Over the past four decades, treatment of acute leukemia in children has made remarkable progress, from this disease being lethal to now achieving cure rates of 80% for acute lymphoblastic leukemia and 45% for acute myeloid leukemia. This progress is largely owed to the optimization of existing treatment modalities rather than the discovery of new agents. However, the annual number of patients with leukemia who experience relapse after initial therapy remains greater than that of new cases of most childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize medications and tailor treatment regimens to individual patients, with the goal of enhancing efficacy and safety through better understanding of the person's genetic makeup. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute leukemia. These include work using candidate-gene approaches, as well as genome-wide studies using haplotype mapping and gene expression profiling. These strategies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm.
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    THE PROTEASOME AND PROTEASOME INHIBITORS IN CANCER THERAPY (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 189-213 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
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    MOLECULAR MECHANISM OF 7TM RECEPTOR ACTIVATIONĐ??A GLOBAL TOGGLE SWITCH MODEL (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 481-519 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VIĐ??and to some degree TM-VIIĐ??around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.
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    FUNCTION OF RETINOID NUCLEAR RECEPTORS: Lessons from Genetic and Pharmacological Dissections of the Retinoic Acid Signaling Pathway During Mouse Embryogenesis (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 451-480 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Retinoic acid (RA) is involved in vertebrate morphogenesis, growth, cellular differentiation, and tissue homeostasis. The use of in vitro systems initially led to the identification of nuclear receptor RXR/RAR heterodimers as possible transducers of the RA signal. To unveil the physiological functions of RARs and RXRs, genetic and pharmacological studies have been performed in the mouse. Together, their results demonstrate that (a) RXR/RAR heterodimers in which RXR is either transcriptionally active or silent are involved in the transduction of the RA signal during prenatal development, (b) specific RXRʼ̛/RAR heterodimers are required at many distinct stages during early embryogenesis and organogenesis, (c) the physiological role of RA and its receptors cannot be extrapolated from teratogenesis studies using retinoids in excess. Additional cell typeĐ??restricted and temporally controlled somatic mutagenesis is required to determine the functions of RARs and RXRs during postnatal life.
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    CANNABINOID RECEPTORS AS THERAPEUTIC TARGETS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 101-122 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G proteinĐ??coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.
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    REGULATION OF PLATELET FUNCTIONS BY P2 RECEPTORS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 277-300 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The main role of blood platelets is to ensure primary hemostasis, which is the maintenance of vessel integrity and cessation of bleeding upon injury. While playing a major part in acute arterial thrombosis, platelets are also involved in inflammation, atherosclerosis, and angiogenesis. ADP and ATP play a crucial role in platelet activation, and their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G proteinĐ??coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus. Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs such as clopidogrel. Studies in P2Y1 and P2X1 knockout mice and selective P2Y1 and P2X1 antagonists have shown that these receptors are also attractive targets for new antithrombotic compounds. The potential role of platelet P2 receptors in the involvement of platelets in inflammatory processes is also discussed.
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    FUNCTIONAL IMAGING OF TUMOR PROTEOLYSIS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 301-315 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The roles of proteases in cancer are now known to be much broader than simply degradation of extracellular matrix during tumor invasion and metastasis. Furthermore, proteases from tumor-associated cells (e.g., fibroblasts, inflammatory cells, endothelial cells) as well as tumor cells are recognized to contribute to pathways critical to neoplastic progression. Although elevated expression (transcripts and proteins) of proteases, and in some cases protease inhibitors, has been documented in many tumors, techniques to assess functional roles for proteases require that we measure protease activity and inhibition of that activity rather than levels of proteases, activators, and inhibitors. Novel techniques for functional imaging of protease activity, both in vitro and in vivo, are being developed as are imaging probes that will allow us to determine protease activity and in some cases to discriminate among protease activities. These should be useful clinically as surrogate endpoints for therapies that alter protease activities.
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    ROLE OF ABCG2/BCRP IN BIOLOGY AND MEDICINE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 381-410 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The protein variously named ABCG2/BCRP/MXR/ABCP is a recently described ATP-binding cassette (ABC) transporter originally identified by its ability to confer drug resistance that is independent of Mrp1 (multidrug-resistance protein 1) and Pgp (P-glycoprotein). Unlike Mrp1 and Pgp, ABCG2 is a half-transporter that must homodimerize to acquire transport activity. ABCG2 is found in a variety of stem cells and may protect them from exogenous and endogenous toxins. ABCG2 expression is upregulated under low-oxygen conditions, consistent with its high expression in tissues exposed to low-oxygen environments. ABCG2 interacts with heme and other porphyrins and protects cells and/or tissues from protoporphyrin accumulation under hypoxic conditions. Individuals who carry ABCG2 alleles that have impaired function may be more susceptible to porphyrin-induced toxicity. Abcg2 knock-out models have allowed in vivo studies of Abcg2 function in host and cellular defense. In combination with immunohistochemical analyses, these studies have revealed how ABCG2 influences the absorption, distribution, and excretion of drugs and cytotoxins.
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    ACCESSORY PROTEINS FOR G PROTEINS: Partners in Signaling (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 151-187 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Accessory proteins involved in signal processing through heterotrimeric G proteins are generally defined as proteins distinct from G proteinĐ??coupled receptor (GPCR), G protein, or classical effectors that regulate the strength/efficiency/specificity of signal transfer upon receptor activation or position these entities in the right microenvironment, contributing to the formation of a functional signal transduction complex. A flurry of recent studies have implicated an additional class of accessory proteins for this system that provide signal input to heterotrimeric G proteins in the absence of a cell surface receptor, serve as alternative binding partners for G protein subunits, provide unexpected modes of G protein regulation, and have introduced additional functional roles for G proteins. This group of accessory proteins includes the recently discovered Activators of G protein Signaling (AGS) proteins identified in a functional screen for receptor-independent activators of G protein signaling as well as several proteins identified in protein interaction screens and genetic screens in model organisms. These accessory proteins may influence GDP dissociation and nucleotide exchange at the G subunit, alter subunit interactions within heterotrimeric G independent of nucleotide exchange, or form complexes with G or G independent of the typical G heterotrimer. AGS and related accessory proteins reveal unexpected diversity in G protein subunits as signal transducers within the cell.
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    THE LYMPHATIC VASCULATURE: Recent Progress and Paradigms (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 457-483 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The field of lymphatic research has been recently invigorated by the identification of genes and mechanisms that control various aspects of lymphatic development. We are beginning to understand how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner. The generation of genetically engineered mice with defects in different steps of the lymphangiogenic program has provided models that are increasing our understanding of the lymphatic system in health and disease. This knowledge, in turn, should lead to the development of better diagnostic methods and treatments of lymphatic disorders and tumor metastasis.
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    IN AWE OF SUBCELLULAR COMPLEXITY: 50 Years of Trespassing Boundaries Within the Cell (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 1-33 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In this review I describe the several stages of my research career, all of which were driven by a desire to understand the basic mechanisms responsible for the complex and beautiful organization of the eukaryotic cell. I was originally trained as an electron microscopist in Argentina, and my first major contribution was the introduction of glutaraldehyde as a fixative that preserved the fine structure of cells, which opened the way for cytochemical studies at the EM level. My subsequent work on membrane-bound ribosomes illuminated the process of cotranslational translocation of polypeptides across the ER membrane and led to the formulation, with Gunter Blobel, of the signal hypothesis. My later studies with many talented colleagues contributed to an understanding of ER structure and function and aspects of the mechanisms that generate and maintain the polarity of epithelial cells. For this work my laboratory introduced the now widely adopted Madin-Darby canine kidney (MDCK) cell line, and demonstrated the polarized budding of envelope viruses from those cells, providing a powerful new system that further advanced the field of protein traffic.
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    ASSEMBLY OF VARIANT HISTONES INTO CHROMATIN (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 133-153 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Chromatin can be differentiated by the deposition of variant histones at centromeres, active genes, and silent loci. Variant histones are assembled into nucleosomes in a replication-independent manner, in contrast to assembly of bulk chromatin that is coupled to replication. Recent in vitro studies have provided the first glimpses of protein machines dedicated to building and replacing alternative nucleosomes. They deposit variant H2A and H3 histones and are targeted to particular functional sites in the genome. Differences between variant and canonical histones can have profound consequences, either for delivery of the histones to sites of assembly or for their function after incorporation into chromatin. Recent studies have also revealed connections between assembly of variant nucleosomes, chromatin remodeling, and histone post-translational modification. Taken together, these findings indicate that chromosome architecture can be highly dynamic at the most fundamental level, with epigenetic consequences.
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    ANISOTROPIC EXPANSION OF THE PLANT CELL WALL (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 203-222 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Plants shape their organs with a precision demanded by optimal function; organ shaping requires control over cell wall expansion anisotropy. Focusing on multicellular organs, I survey the occurrence of expansion anisotropy and discuss its causes and proposed controls. Expansion anisotropy of a unit area of cell wall is characterized by the direction and degree of anisotropy. The direction of maximal expansion rate is usually regulated by the direction of net alignment among cellulose microfibrils, which overcomes the prevailing stress anisotropy. In some stems, the directionality of expansion of epidermal cells is controlled by that of the inner tissue. The degree of anisotropy can vary widely as a function of position and of treatment. The degree of anisotropy is probably controlled by factors in addition to the direction of microfibril alignment. I hypothesize that rates of expansion in maximal and minimal directions are regulated by distinct molecular mechanisms that regulate interactions between matrix and microfibrils.
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    IN VIVO IMAGING OF LYMPHOCYTE TRAFFICKING (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 581-603 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Over the past decades, intravital microscopy (IVM), the imaging of cells in living organisms, has become a valuable tool for studying the molecular determinants of lymphocyte trafficking. Recent advances in microscopy now make it possible to image cell migration and cell-cell interactions in vivo deep within intact tissues. Here, we summarize the principal techniques that are currently used in IVM, discuss options and tools for fluorescence-based visualization of lymphocytes in microvessels and tissues, and describe IVM models used to explore lymphoid and non-lymphoid organs. The latter will be introduced according to the physiologic itinerary of developing and differentiating T and B lymphocytes as they traffic through the body, beginning with their development in bone marrow and thymus and continuing with their migration to secondary lymphoid organs and peripheral tissues.
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    CENTROSOMES IN CELLULAR REGULATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 411-434 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Centrosomes, spindle pole bodies, and related structures in other organisms are a morphologically diverse group of organelles that share a common ability to nucleate and organize microtubules and are thus referred to as microtubule organizing centers or MTOCs. Features associated with MTOCs include organization of mitotic spindles, formation of primary cilia, progression through cytokinesis, and self-duplication once per cell cycle. Centrosomes bind more than 100 regulatory proteins, whose identities suggest roles in a multitude of cellular functions. In fact, recent work has shown that MTOCs are required for several regulatory functions including cell cycle transitions, cellular responses to stress, and organization of signal transduction pathways. These new liaisons between MTOCs and cellular regulation are the focus of this review. Elucidation of these and other previously unappreciated centrosome functions promises to yield exciting scientific discovery for some time to come.
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    THE GREAT ESCAPE: When Cancer Cells Hijack the Genes for Chemotaxis and Motility (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 695-718 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The combined use of the new technologies of multiphoton-based intravital imaging, the chemotaxis-mediated collection of invasive cells, and high sensitivity expression profiling has allowed the correlation of the behavior of invasive tumor cells in vivo with their gene expression patterns. New insights have resulted including a gene expression signature for invasive cells and the tumor microenvironment invasion model. This model proposes that tumor invasion and metastasis can be studied as a problem resembling normal morphogenesis. We discuss how these new insights may lead to a better understanding of the molecular basis of the invasive behavior of tumor cells in vivo, which may result in new strategies for the diagnosis and treatment of metastasis.
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    ENDOPLASMIC RETICULUMĐ??ASSOCIATED DEGRADATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 435-456 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Secretory and transmembrane proteins enter the secretory pathway through the protein-conducting Sec61 channel in the membrane of the endoplasmic reticulum. In the endoplasmic reticulum, proteins fold, are frequently covalently modified, and oligomerize before they are packaged into transport vesicles that shuttle them to the Golgi complex. Proteins that misfold in the endoplasmic reticulum are selectively transported back across the endoplasmic reticulum membrane to the cytosol for degradation by proteasomes. Depending on the topology of the defect in the protein, cytosolic or lumenal chaperones are involved in its targeting to degradation. The export channel for misfolded proteins is likely also formed by Sec61p. Export may be powered by AAA-ATPases of the proteasome 19S regulatory particle or Cdc48p/p97. Exported proteins are frequently ubiquitylated prior to degradation and are escorted to the proteasome by polyubiquitin-binding proteins.
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    PHAGOCYTOSIS: At the Crossroads of Innate and Adaptive Immunity (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 511-527 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Phagocytosis, the process by which cells engulf large particles, requires a substantial contribution of membranes. Recent studies have revealed that intracellular compartments, including endocytic organelles and the endoplasmic reticulum (ER), can engage in fusion events with the plasma membrane at the sites of nascent phagosomes. The finding that ER proteins are delivered to phagosomes, where degraded peptides are loaded onto major histocompatibility complex (MHC) class II molecules, has significantly enhanced our understanding of the immune functions associated with these organelles. Although it is well known that pathogens are killed in phagosomes, the contribution of ER proteins to phagosomes has provided a novel pathway for the loading of exogenous peptides onto MHC class I molecules, a process known as cross-presentation. Thus, phagocytosis has evolved from a nutritional function in unicellular organisms to play key roles in both innate and adaptive immunity in vertebrates.
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    RETINOTECTAL MAPPING: New Insights from Molecular Genetics (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 551-580 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The sensory and motor components of nervous systems are connected topographically and contain neural maps of the external world. The paradigm for such maps is the precisely ordered wiring of the output cells of the eye to their synaptic targets in the tectum of the midbrain. The retinotectal map is organized in development through the graded activity of Eph receptor tyrosine kinases and their ephrin ligands. These signaling proteins are arrayed in complementary expression gradients along the orthogonal axes of the retina and tectum, and provide both input and recipient cells with Cartesian coordinates that specify their location. Molecular genetic studies in the mouse indicate that these coordinates are interpreted in the context of neuronal competition for termination sites in the tectum. They further suggest that order in the retinotectal map is determined by ratiometric rather than absolute difference comparisons in Eph signaling along the temporal-nasal and dorsal-ventral axes of the eye.
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    SPATIAL CONTROL OF CELL EXPANSION BY THE PLANT CYTOSKELETON (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 271-295 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The cytoskeleton plays important roles in plant cell shape determination by influencing the patterns in which cell wall materials are deposited. Cortical microtubules are thought to orient the direction of cell expansion primarily via their influence on the deposition of cellulose into the wall, although the precise nature of the microtubule-cellulose relationship remains unclear. In both tip-growing and diffusely growing cell types, F-actin promotes growth and also contributes to the spatial regulation of growth. F-actin has been proposed to play a variety of roles in the regulation of secretion in expanding cells, but its functions in cell growth control are not well understood. Recent work highlighted in this review on the morphogenesis of selected cell types has yielded substantial new insights into mechanisms governing the dynamics and organization of cytoskeletal filaments in expanding plant cells and how microtubules and F-actin interact to direct patterns of cell growth. Nevertheless, many important questions remain to be answered.
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    REGULATION OF ROOT APICAL MERISTEM DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 485-509 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The establishment of the Angiosperm root apical meristem is dependent on the specification of a stem cell niche and the subsequent development of the quiescent center at the presumptive root pole. Distribution of auxin and the establishment of auxin maxima are early formative steps in niche specification that depend on the expression and distribution of auxin carriers. Auxin specifies stem cell niche formation by directly and indirectly affecting gene activities. Part of the indirect regulation by auxin may involve changes in redox, favoring local, oxidized microenvironments. Formation of a QC is required for root meristem development and elaboration. Many signals likely pass between the QC and the adjacent root meristem tissues. Disappearance of the QC is associated with roots becoming determinate. Given the many auxin feedback loops, we hypothesize that roots evolved as part of an auxin homeostasis mechanism.
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    PLANAR CELL POLARIZATION: An Emerging Model Points in the Right Direction (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 155-176 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Polarization is a feature common to many cell types. Epithelial cells, for example, exhibit a characteristic apical-basolateral polarity that is critical for their function. In addition to this ubiquitous form of polarity, whole fields of cells are often polarized in a plane perpendicular to the apical-basal axis. This form of polarity, referred to as planar cell polarity (PCP), exists in all adult Drosophila cuticular tissues, as well as in numerous vertebrate tissues, including the mammalian skin and inner ear epithelia. Recent advances in the study of PCP establishment are beginning to unravel the molecular mechanisms underlying this cellular process. This review discusses new developments in the molecular understanding of PCP in Drosophila and vertebrates and integrates the current data in a model to illustrate how interactions between PCP factors might function to generate planar polarity.
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    DOCOSAHEXAENOIC ACID, FATTY ACIDĐ??INTERACTING PROTEINS, AND NEURONAL FUNCTION: Breastmilk and Fish Are Good for You (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 633-657 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In contrast to other tissues, the nervous system is enriched in the polyunsaturated fatty acids (PUFAs): arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3). Despite their abundance in the nervous system, AA and DHA cannot be synthesized de novo by mammals; they, or their precursors, must be ingested from dietary sources and transported to the brain. During late gestation and the early postnatal period, neurodevelopment is exceptionally rapid, and substantial amounts of PUFAs, especially DHA, are critical to ensure neurite outgrowth as well as proper brain and retina development. Here, we review the various functions of DHA in the nervous system, the proteins involved in its internalization and metabolism into phospholipids, and its relationship to several neurological disorders, including Alzheimer's disease and depression.
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    QUORUM SENSING: Cell-to-Cell Communication in Bacteria (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 319-346 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Bacteria communicate with one another using chemical signal molecules. As in higher organisms, the information supplied by these molecules is critical for synchronizing the activities of large groups of cells. In bacteria, chemical communication involves producing, releasing, detecting, and responding to small hormone-like molecules termed autoinducers . This process, termed quorum sensing, allows bacteria to monitor the environment for other bacteria and to alter behavior on a population-wide scale in response to changes in the number and/or species present in a community. Most quorum-sensing-controlled processes are unproductive when undertaken by an individual bacterium acting alone but become beneficial when carried out simultaneously by a large number of cells. Thus, quorum sensing confuses the distinction between prokaryotes and eukaryotes because it enables bacteria to act as multicellular organisms. This review focuses on the architectures of bacterial chemical communication networks; how chemical information is integrated, processed, and transduced to control gene expression; how intra- and interspecies cell-cell communication is accomplished; and the intriguing possibility of prokaryote-eukaryote cross-communication.
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    MOLECULAR MECHANISMS OF STEROID HORMONE SIGNALING IN PLANTS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 177-201 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Brassinosteroids (BRs), the polyhydroxylated steroid hormones of plants, regulate the growth and differentiation of plants throughout their life cycle. Over the past several years, genetic and biochemical approaches have yielded great progress in understanding BR signaling. Unlike their animal counterparts, BRs are perceived at the plasma membrane by direct binding to the extracellular domain of the BRI1 receptor S/T kinase. BR perception initiates a signaling cascade, acting through a GSK3 kinase, BIN2, and the BSU1 phosphatase, which in turn modulates the phosphorylation state and stability of the nuclear transcription factors BES1 and BZR1. Microarray technology has been used extensively to provide a global view of BR genomic effects, as well as a specific set of target genes for BES1 and BZR1. These gene products thus provide a framework for how BRs regulate the growth of plants.
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    INTEGRIN STRUCTURE, ALLOSTERY, AND BIDIRECTIONAL SIGNALING (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 381-410 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: ʼ̛?‚ heterodimeric integrins mediate dynamic adhesive cell-cell and cell-extracellular matrix (ECM) interactions in metazoa that are critical in growth and development, hemostasis, and host defense. A central feature of these receptors is their capacity to change rapidly and reversibly their adhesive functions by modulating their ligand-binding affinity. This is normally achieved through interactions of the short cytoplasmic integrin tails with intracellular proteins, which trigger restructuring of the ligand-binding site through long-range conformational changes in the ectodomain. Ligand binding in turn elicits conformational changes that are transmitted back to the cell to regulate diverse responses. The publication of the integrin ʼ̛V?‚3 crystal structure has provided the context for interpreting decades-old biochemical studies. Newer NMR, crystallographic, and EM data, reviewed here, are providing a better picture of the dynamic integrin structure and the allosteric changes that guide its diverse functions.
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    CAJAL BODIES: A Long History of Discovery (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 105-131 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: This review surveys what is known about the structure and function of the subnuclear domains called Cajal bodies (CBs). The major focus is on CBs in mammalian cells but we provide an overview of homologous CB structures in other organisms. We discuss the protein and RNA components of CBs, including factors recently found to associate in a cell cycle-dependent fashion or under specific metabolic or stress conditions. We also consider the dynamic properties of both CBs and their molecular components, based largely on recent data obtained thanks to the advent of improved in vivo detection and imaging methods. We discuss how these data contribute to an understanding of CB functions and highlight major questions that remain to be answered. Finally, we consider the interesting links that have emerged between CBs and alterations in nuclear structure apparent in a range of human pathologies, including cancer and inherited neurodegenerative diseases. We speculate on the relationship between CB function and molecular disease.
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    REGULATION OF PROTEIN ACTIVITIES BY PHOSPHOINOSITIDE PHOSPHATES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 57-79 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Phosphoinositide phosphates (PIPs) correspond to phosphorylated derivatives of phosphatidylinositol (PI). Despite their relatively low abundance in the plasma membrane, PIPs play a crucial role as precursors of second messengers and are themselves important signaling and targeting molecules. Indeed, modulation of levels of PIPs affects, for example, cortical actin organization, membrane dynamics, and cell migration. The focus of this review is on selected interesting targets of PIPs. Those proteins that bind PIPs and are involved in regulation of actin assembly, actin membrane linkage, and actin contractility are discussed, as well as those that are involved in signaling, such as small GTPases, protein kinases, and phosphatases, or in regulation of membrane dynamics.
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    RNA TRANSPORT AND LOCAL CONTROL OF TRANSLATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 223-245 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In eukaryotes, the entwined pathways of RNA transport and local translational regulation are key determinants in the spatio-temporal articulation of gene expression. One of the main advantages of this mechanism over transcriptional control in the nucleus lies in the fact that it endows local sites with independent decision-making authority, a consideration that is of particular relevance in cells with complex cellular architecture such as neurons. Localized RNAs typically contain codes, expressed within cis-acting elements, that specify subcellular targeting. Such codes are recognized by trans-acting factors, adaptors that mediate translocation along cytoskeletal elements by molecular motors. Most transported mRNAs are assumed translationally dormant while en route. In some cell types, especially in neurons, it is considered crucial that translation remains repressed after arrival at the destination site (e.g., a postsynaptic microdomain) until an appropriate activation signal is received. Several candidate mechanisms have been suggested to participate in the local implementation of translational repression and activation, and such mechanisms may target translation at the level of initiation and/or elongation. Recent data indicate that untranslated RNAs may play important roles in the local control of translation.
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    RHO GTPASES: Biochemistry and Biology (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 247-269 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.020604.150721
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    PROTEIN TRANSLOCATION BY THE SEC61/SECY CHANNEL (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 529-550 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The conserved protein-conducting channel, referred to as the Sec61 channel in eukaryotes or the SecY channel in eubacteria and archaea, translocates proteins across cellular membranes and integrates proteins containing hydrophobic transmembrane segments into lipid bilayers. Structural studies illustrate how the protein-conducting channel accomplishes these tasks. Three different mechanisms, each requiring a different set of channel binding partners, are employed to move polypeptide substrates: The ribosome feeds the polypeptide chain directly into the channel, a ratcheting mechanism is used by the eukaryotic endoplasmic reticulum chaperone BiP, and a pushing mechanism is utilized by the bacterial ATPase SecA. We review these translocation mechanisms, relating biochemical and genetic observations to the structures of the protein-conducting channel and its binding partners.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.133214
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    MECHANISMS OF APOPTOSIS THROUGH STRUCTURAL BIOLOGY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 35-56 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Apoptosis plays a central role in the development and homeostasis of metazoans. Research in the past two decades has led to the identification of hundreds of genes that govern the initiation, execution, and regulation of apoptosis. An earlier focus on the genetic and cell biological characterization has now been complemented by systematic biochemical and structural investigation, giving rise to an unprecedented level of clarity in many aspects of apoptosis. In this review, we focus on the molecular mechanisms of apoptosis by synthesizing available biochemical and structural information. We discuss the mechanisms of ligand binding to death receptors, actions of the Bcl-2 family of proteins, and caspase activation, inhibition, and removal of inhibition. Although an emphasis is given to the mammalian pathways, a comparative analysis is applied to related mechanistic information in Drosophila and Caenorhabditis elegans.
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    PUSHING THE ENVELOPE: Structure, Function, and Dynamics of the Nuclear Periphery (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 347-380 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The nuclear envelope (NE) is a highly specialized membrane that delineates the eukaryotic cell nucleus. It is composed of the inner and outer nuclear membranes, nuclear pore complexes (NPCs) and, in metazoa, the lamina. The NE not only regulates the trafficking of macromolecules between nucleoplasm and cytosol but also provides anchoring sites for chromatin and the cytoskeleton. Through these interactions, the NE helps position the nucleus within the cell and chromosomes within the nucleus, thereby regulating the expression of certain genes. The NE is not static, rather it is continuously remodeled during cell division. The most dramatic example of NE reorganization occurs during mitosis in metazoa when the NE undergoes a complete cycle of disassembly and reformation. Despite the importance of the NE for eukaryotic cell life, relatively little is known about its biogenesis or many of its functions. We thus are far from understanding the molecular etiology of a diverse group of NE-associated diseases.
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    STEM CELL NICHE: Structure and Function (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 605-631 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Adult tissue-specific stem cells have the capacity to self-renew and generate functional differentiated cells that replenish lost cells throughout an organism's lifetime. Studies on stem cells from diverse systems have shown that stem cell function is controlled by extracellular cues from the niche and by intrinsic genetic programs within the stem cell. Here, we review the remarkable progress recently made in research regarding the stem cell niche. We compare the differences and commonalities of different stem cell niches in Drosophila ovary/testis and Caenorhabditis elegans distal tip, as well as in mammalian bone marrow, skin/hair follicle, intestine, brain, and testis. On the basis of this comparison, we summarize the common features, structure, and functions of the stem cell niche and highlight important niche signals that are conserved from Drosophila to mammals. We hope this comparative summary defines the basic elements of the stem cell niche, providing guiding principles for identification of the niche in other systems and pointing to areas for future studies.
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    SPECIFICITY AND VERSATILITY IN TGF-?‚ SIGNALING THROUGH SMADS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 659-693 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The TGF-?‚ family comprises many structurally related differentiation factors that act through a heteromeric receptor complex at the cell surface and an intracellular signal transducing Smad complex. The receptor complex consists of two type II and two type I transmembrane serine/threonine kinases. Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression. The vertebrate genome encodes many ligands, fewer type II and type I receptors, and only a few Smads. In contrast to the perceived simplicity of the signal transduction mechanism with few Smads, the cellular responses to TGF-?‚ ligands are complex and context dependent. This raises the question of how the specificity of the ligand-induced signaling is achieved. We review the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.022404.142018
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    PRINCIPLES OF LYSOSOMAL MEMBRANE DIGESTION: Stimulation of Sphingolipid Degradation by Sphingolipid Activator Proteins and Anionic Lysosomal Lipids (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 81-103 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Sphingolipids and glycosphingolipids are membrane components of eukaryotic cell surfaces. Their constitutive degradation takes place on the surface of intra-endosomal and intra-lysosomal membrane structures. During endocytosis, these intra-lysosomal membranes are formed and prepared for digestion by a lipid-sorting process during which their cholesterol content decreases and the concentration of the negatively charged bis(monoacylglycero)phosphate (BMP)Đ??erroneously also called lysobisphosphatidic acid (LBPA)Đ??increases. Glycosphingolipid degradation requires the presence of water-soluble acid exohydrolases, sphingolipid activator proteins, and anionic phospholipids like BMP. The lysosomal degradation of sphingolipids with short hydrophilic head groups requires the presence of sphingolipid activator proteins (SAPs). These are the saposins (Saps) and the GM2 activator protein. Sphingolipid activator proteins are membrane-perturbing and lipid-binding proteins with different specificities for the bound lipid and the activated enzyme-catalyzed reaction. Their inherited deficiency leads to sphingolipid- and membrane-storage diseases. Sphingolipid activator proteins not only facilitate glycolipid digestion but also act as glycolipid transfer proteins facilitating the association of lipid antigens with immunoreceptors of the CD1 family.
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    RNA SILENCING SYSTEMS AND THEIR RELEVANCE TO PLANT DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 297-318 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: RNA silencing refers to a broad range of phenomena sharing the common feature that large, double-stranded RNAs or stem-loop precursors are processed to ca. 21Đ??26 nucleotide small RNAs, which then guide the cleavage of cognate RNAs, block productive translation of these RNAs, or induce methylation of specific target DNAs. Although the core mechanisms are evolutionarily conserved, epigenetic maintenance of silencing by amplification of small RNAs and the elaboration of mobile, RNA-based silencing signals occur predominantly in plants. Plant RNA silencing systems are organized into a network with shared components and overlapping functions. MicroRNAs, and probably trans-acting small RNAs, help regulate development at the posttranscriptional level. Small interfering RNAs associated with transgene- and virus-induced silencing function primarily in defending against foreign nucleic acids. Another system, which is concerned with RNA-directed methylation of DNA repeats, seems to have roles in epigenetic silencing of certain transposable elements and genes under their control.
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    MARGINAL ZONE B CELLS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 161-196 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Our views regarding the origins and functions of splenic marginal zone B cells have changed considerably over the past few years. Perspectives regarding the development and function of these cells vary considerably between investigators studying human and rodent immunology. Marginal zone B cells are now recognized to constitute a distinct naive B lymphoid lineage. Considerable progress has been made regarding the mechanisms involved in marginal zone B cell development in the mouse. Many of the molecular events that participate in the retention of this lineage of B cells in the marginal zone have been identified. Here, we discuss the functions of these cells in both innate and adaptive immunity. We also attempt to reconcile differing viewpoints regarding the generation and function of marginal zone B cells in rodents and primates.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115728
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    ANTIGEN-SPECIFIC MEMORY B CELL DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 487-513 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Helper T (Th) cellĐ??regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cellĐ??B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.
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    B CELL SIGNALING AND Tumorigenesis (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 415-445 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The proliferation and differentiation of lymphocytes are regulated by receptors localized on the cell surface. Engagement of these receptors induces the activation of intracellular signaling proteins that transmit the receptor signals to distinct targets and control the cellular responses. The first signaling proteins to be discovered in higher organisms were the products of oncogenes. For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes. Now, as many cellular signaling molecules have been discovered and ordered into certain pathways, we can better understand why particular signaling proteins are associated with tumorigenesis. In this review, we discuss recent progress in unraveling the molecular mechanisms of signaling pathways that control the proliferation and differentiation of early B cells. We point out the concepts of auto-inhibition and subcellular localization as crucial aspects in the regulation of B cell signaling.
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    IMMUNOLOGY OF MULTIPLE SCLEROSIS * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 683-747 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.
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    UNDERSTANDING PRESENTATION OF VIRAL ANTIGENS TO CD8+ T CELLS IN VIVO: The Key to Rational Vaccine Design * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 651-682 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: CD8+ T cells play a critical role in antiviral immunity by exerting direct antiviral activity against infected cells. Because of their ability to recognize all types of viral proteins, they offer the promise of providing broad immunity to viruses that evade humoral immunity by varying their surface proteins. Consequently, there is considerable interest in developing vaccines that elicit effective antiviral TCD8+ responses. Generating optimal vaccines ultimately requires rational design based on detailed knowledge of how TCD8+ are activated in vivo under natural circumstances. Here we review recent progress obtained largely by in vivo studies in mice to understand the mechanistic basis for activation of naive TCD8+ in virus infections. These studies point the way to detailed understanding and provide some key information for vaccine development, although much remains to be learned to enable truly rational vaccine design.
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    REGULATION OF LYMPHOID DEVELOPMENT, DIFFERENTIATION, AND FUNCTION BY THE NOTCH PATHWAY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 945-974 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The Notch pathway is gaining increasing recognition as a key regulator of developmental choices, differentiation, and function throughout the hematolymphoid system. Notch controls the generation of hematopoietic stem cells during embryonic development and may affect their subsequent homeostasis. Commitment to the T??cell lineage and subsequent stages of early thymopoiesis is critically regulated by Notch. Recent data indicate that Notch can also direct the differentiation and activity of peripheral T and B cells. Thus, the full spectrum of Notch effects is just beginning to be understood. In this review, we discuss this explosion of knowledge as well as current controversies and challenges in the field.
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    PETER HOCHACHKA: Adventures in Biochemical Adaptation (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 25-37 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Peter Hochachka was one of the most creative forces in the field of comparative physiology during the past half-century. His career was truly an exploratory adventure, in both intellectual and geographic senses. His broad comparative studies of metabolism in organisms as diverse as trout, tunas, oysters, squid, turtles, locusts, hummingbirds, seals, and humans revealed the adaptable features of enzymes and metabolic pathways that provide the biochemical bases for diverse lifestyles and environments. In its combined breadth and depth, no other corpus of work better illustrates the principle of "unity in diversity" that marks comparative physiology. Through his publications, his stimulating mentorship, his broad editorial services, and his continuousĐ??and highly infectiousĐ??enthusiasm for his field, Peter Hochachka served as one of the most influential leaders in the transformation of comparative physiology.
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    UNLOCKING THE SECRETS OF CELL SIGNALING (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 1-21 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: My scientific life has been spent trying to understand how cells communicate with each other. This interest in cell signaling began with studies on the control of fluid secretion by an insect salivary gland, and the subsequent quest led to the discovery of inositol trisphosphate (IP3) and its role in calcium signaling, which effectively divided my scientific career into two distinct parts. The first part was primarily experimental and culminated in the discovery of IP3, which set the agenda for the second half during which I have enjoyed exploring the many functions of this remarkably versatile signaling system. It has been particularly exciting to find out how this IP3/Ca2+ signaling pathway has been adapted to control processes as diverse as fertilization, proliferation, cell contraction, secretion, and information processing in neuronal cells.
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    RNAI AS AN EXPERIMENTAL AND THERAPEUTIC TOOL TO STUDY AND REGULATE PHYSIOLOGICAL AND DISEASE PROCESSES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 147-173 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Over the past four years RNA interference (RNAi) has exploded onto the research scene as a new approach to manipulate gene expression in mammalian systems. More recently, RNAi has garnered much interest as a potential therapeutic strategy. In this review, we briefly summarize the current understanding of RNAi biology and examine how RNAi has been used to study the genetic basis of physiological and disease processes in mammalian systems. We also explore some of the new developments in the use of RNAi for disease therapy and highlight the key challenges that currently limit its application in the laboratory, as well as in the clinical setting.
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    ENDOCRINOLOGY OF THE STRESS RESPONSE 1 (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 259-284 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides ʼ̛-melanocyte-stimulating hormone and ?‚-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.
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    LESSONS IN ESTROGEN BIOLOGY FROM KNOCKOUT AND TRANSGENIC ANIMALS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 285-308 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Tremendous progress has been made in elucidating numerous critical aspects of estrogen signaling. New tools and techniques have enabled detailed molecular analysis of components that direct estrogen responses. At the other end of the spectrum, generation of a multiplicity of transgenic animals has allowed analysis of the physiological roles of the estrogen-signaling components in biologically relevant models. Here, we review the ever-increasing body of knowledge in the field of estrogen biology, especially as applied to the female reproductive processes.
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    MECHANISMS OF BICARBONATE SECRETION IN THE PANCREATIC DUCT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 377-409 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: In many species the pancreatic duct epithelium secretes HCO3 ions at a concentration of around 140 mM by a mechanism that is only partially understood. We know that HCO3 uptake at the basolateral membrane is achieved by Na+-HCO3 cotransport and also by a H+-ATPase and Na+/H+ exchanger operating together with carbonic anhydrase. At the apical membrane, the secretion of moderate concentrations of HCO3 can be explained by the parallel activity of a Cl/HCO3 exchanger and a Cl conductance, either the cystic fibrosis transmembrane conductance regulator (CFTR) or a Ca2+-activated Cl channel (CaCC). However, the sustained secretion of HCO3 into a HCO3 -rich luminal fluid cannot be explained by conventional Cl/HCO3 exchange. HCO3 efflux across the apical membrane is an electrogenic process that is facilitated by the depletion of intracellular Cl, but it remains to be seen whether it is mediated predominantly by CFTR or by an electrogenic SLC26 anion exchanger.
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    SECRETION AND ABSORPTION BY COLONIC CRYPTS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 471-490 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The intestines play an important role in the absorption and secretion of nutrients. The colon is the final area for recapturing electrolytes and water prior to excretion, and in order to maintain this electrolyte homeostasis, a complex interaction between secretory and absorptive processes is necessary. Until recently it was thought that secretion and absorption were two distinct processes associated with either crypts or surface cells, respectively. Recently it was demonstrated that both the surface and crypt cells can perform secretory and absorptive functions and that, in fact, these functions can be going on simultaneously. This issue is important in the complexities associated with secretory diarrhea and also in attempting to develop treatment strategies for intestinal disorders. Here, we update the model of colonic secretion and absorption, discuss new issues of transporter activation, and identify some important new receptor pathways that are important modulators of the secretory and absorptive functions of the colon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.031103.153530
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    NOVEL RENAL AMINO ACID TRANSPORTERS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 557-572 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Reabsorption of amino acids, similar to that of glucose, is a major task of the proximal kidney tubule. Various amino acids are actively transported across the luminal brush border membrane into proximal tubule epithelial cells, most of which by cotransport. An important player is the newly identified cotransporter (symporter) B0AT1 (SLC6A19), which imports a broad range of neutral amino acids together with Na+ across the luminal membrane and which is defective in Hartnup disorder. In contrast, cationic amino acids and cystine are taken up in exchange for recycled neutral amino acids by the heterodimeric cystinuria transporter. The basolateral release of some neutral amino acids into the extracellular space is mediated by unidirectional efflux transporters, analogous to GLUT2, that have not yet been definitively identified. Additionally, cationic amino acids and some other neutral amino acids leave the cell basolaterally via heterodimeric obligatory exchangers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.031103.153949
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    SURFACTANT PROTEIN C BIOSYNTHESIS AND ITS EMERGING ROLE IN CONFORMATIONAL LUNG DISEASE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 663-696 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Surfactant protein C (SP-C) is a hydrophobic 35-amino acid peptide that co-isolates with the phospholipid fraction of lung surfactant. SP-C represents a structurally and functionally challenging protein for the alveolar type 2 cell, which must synthesize, traffic, and process a 191Đ??197-amino acid precursor protein through the regulated secretory pathway. The current understanding of SP-C biosynthesis considers the SP-C proprotein (proSP-C) as a hybrid molecule that incorporates structural and functional features of both bitopic integral membrane proteins and more classically recognized luminal propeptide hormones, which are subject to post-translational processing and regulated exocytosis. Adding to the importance of a detailed understanding of SP-C biosynthesis has been the recent association of mutations in the proSP-C sequence with chronic interstitial pneumonias in children and adults. Many of these mutations involve either missense or deletion mutations located in a region of the proSP-C molecule that has structural homology to the BRI family of proteins linked to inherited degenerative dementias. This review examines the current state of SP-C biosynthesis with a focus on recent developments related to molecular and cellular mechanisms implicated in the emerging role of SP-C mutations in the pathophysiology of diffuse parenchymal lung disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.101937
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    EXOCYTOSIS OF LUNG SURFACTANT: From the Secretory Vesicle to the Air-Liquid Interface (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 595-621 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Exocytosis is fundamental in biology and requires an orchestra of proteins and other constituents to fuse a vesicle with the plasma membrane. Although the molecular fusion machinery appears to be well conserved in evolution, the process itself varies considerably with regard to the diversity of physico-chemical and structural factors that govern the delay between stimulus and fusion, the expansion of the fusion pore, the release of vesicle content, and, finally, its extracellular dispersion. Exocytosis of surfactant is unique in many of these aspects. This review deals with the secretory pathway of pulmonary surfactant from the type II cell to the air-liquid interface, with focus on the distinct mechanisms and regulation of lamellar body (LB) fusion and release. We also discuss the fate of secreted material until it is rearranged into units that finally function to reduce the surface tension in the lung.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.102553
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    FUNCTION OF CHLORIDE CHANNELS IN THE KIDNEY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 759-778 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Numerous Cl channels have been identified in the kidney using physiological approaches and thus are thought to be involved in a range of physiological processes, including vectorial transepithelial Cl transport, cell volume regulation, and vesicular acidification. In addition, expression of genes from several Cl channel gene families has also been observed. However, the molecular characteristics of a number of Cl channels within the kidney are still unknown, and the physiological roles of Cl channels identified by molecular means remain to be determined. A gene knockout approach using mice might shed further light on the characteristics of these various Cl channels. In addition, study of diseases involving Cl channels (channelopathies) might clarify the physiological role of specific Cl channels. To date, more is known about CLC Cl channels than any other Cl channels within the kidney. This review focuses on the physiological roles of CLC Cl channels within the kidney, particularly kidney-specific ClC-K Cl channels, as well as the recently identified maxi anion channel in macula densa, which is involved in tubulo-glomerular feedback.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.032003.153547
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    CALCIUM, THIN FILAMENTS, AND THE INTEGRATIVE BIOLOGY OF CARDIAC CONTRACTILITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 39-67 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although well known as the location of the mechanism by which the cardiac sarcomere is activated by Ca2+ to generate force and shortening, the thin filament is now also recognized as a vital component determining the dynamics of contraction and relaxation. Molecular signaling in the thin filament involves steric, allosteric, and cooperative mechanisms that are modified by protein phosphorylation, sarcomere length and load, the chemical environment, and isoform composition. Approaches employing transgenesis and mutagenesis now permit investigation of these processes at the level of the systems biology of the heart. These studies reveal that the thin filaments are not merely slaves to the levels of Ca2+ determined by membrane channels, transporters and exchangers, but are actively involved in beat to beat control of cardiac function by neural and hormonal factors and by the Frank-Starling mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.114025
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    BIOPHYSICS, PHYSIOLOGICAL ECOLOGY, AND CLIMATE CHANGE: Does Mechanism Matter? (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 177-201 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Recent meta-analyses have shown that the effects of climate change are detectable and significant in their magnitude, but these studies have emphasized the utility of looking for large-scale patterns without necessarily understanding the mechanisms underlying these changes. Using a series of case studies, we explore the potential pitfalls when one fails to incorporate aspects of physiological performance when predicting the consequences of climate change on biotic communities. We argue that by considering the mechanistic details of physiological performance within the context of biophysical ecology (engineering methods of heat, mass and momentum exchange applied to biological systems), such approaches will be better poised to predict where and when the impacts of climate change will most likely occur.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.105027
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    RETINAL PROCESSING NEAR ABSOLUTE THRESHOLD: From Behavior to Mechanism (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 491-514 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Vision at absolute threshold is based on signals produced in a tiny fraction of the rod photoreceptors. This requires that the rods signal the absorption of single photons, and that the resulting signals are transmitted across the retina and encoded in the activity sent from the retina to the brain. Behavioral and ganglion cell sensitivity has often been interpreted to indicate that these biophysical events occur noiselessly, i.e., that vision reaches limits to sensitivity imposed by the division of light into discrete photons and occasional photon-like noise events generated in the rod photoreceptors. We argue that this interpretation is not unique and provide a more conservative view of the constraints behavior and ganglion cell experiments impose on phototransduction and retinal processing. We summarize what is known about how these constraints are met and identify some of the outstanding open issues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.031103.151256
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    LUNG VASCULAR DEVELOPMENT: Implications for the Pathogenesis of Bronchopulmonary Dysplasia (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 623-661 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Past studies have primarily focused on how altered lung vascular growth and development contribute to pulmonary hypertension. Recently, basic studies of vascular growth have led to novel insights into mechanisms underlying development of the normal pulmonary circulation and the essential relationship of vascular growth to lung alveolar development. These observations have led to new concepts underlying the pathobiology of developmental lung disease, especially the inhibition of lung growth that characterizes bronchopulmonary dysplasia (BPD). We speculate that understanding basic mechanisms that regulate and determine vascular growth will lead to new clinical strategies to improve the long-term outcome of premature babies with BPD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.102229
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    CALCIUM-ACTIVATED CHLORIDE CHANNELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 719-758 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Calcium-activated chloride channels (CaCCs) play important roles in cellular physiology, including epithelial secretion of electrolytes and water, sensory transduction, regulation of neuronal and cardiac excitability, and regulation of vascular tone. This review discusses the physiological roles of these channels, their mechanisms of regulation and activation, and the mechanisms of anion selectivity and conduction. Despite the fact that CaCCs are so broadly expressed in cells and play such important functions, understanding these channels has been limited by the absence of specific blockers and the fact that the molecular identities of CaCCs remains in question. Recent status of the pharmacology and molecular identification of CaCCs is evaluated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.032003.154341
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    ASSEMBLY OF FUNCTIONAL CFTR CHLORIDE CHANNELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 701-718 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The assembly of the cystic fibrosis transmembrane regulator (CFTR) chloride channel is of interest from the broad perspective of understanding how ion channels and ABC transporters are formed as well as dealing with the mis-assembly of CFTR in cystic fibrosis. CFTR is functionally distinct from other ABC transporters because it permits bidirectional permeation of anions rather than vectorial transport of solutes. This adaptation of the ABC transporter structure can be rationalized by considering CFTR as a hydrolyzable-ligand-gated channel with cytoplasmic ATP as ligand. Channel gating is initiated by ligand binding when the protein is also phosphorylated by protein kinase A and made reversible by ligand hydrolysis. The two nucleotide-binding sites play different roles in channel activation. CFTR self-associates, possibly as a function of its activation, but most evidence, including the low-resolution three-dimensional structure, indicates that the channel is monomeric. Domain assembly and interaction within the monomer is critical in maturation, stability, and function of the protein. Disease-associated mutations, including the most common, ??F508, interfere with domain folding and association, which occur both co- and post-translationally. Intermolecular interactions of mature CFTR have been detected primarily with the N- and C-terminal tails, and these interactions have some impact not only on channel function but also on localization and processing within the cell. The biosynthetic processing of the nascent polypeptide leading to channel assembly involves transient interactions with numerous chaperones and enzymes on both sides of the endoplasmic reticulum membrane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.032003.154107
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    STRUCTURE AND FUNCTION OF CLC CHANNELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 809-839 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The CLC family comprises a group of integral membrane proteins whose major action is to translocate chloride (Cl) ions across the cell membranes. Recently, the structures of CLC orthologues from two bacterial species, Salmonella typhimurium and Escherichia coli, were solved, providing the first framework for understanding the operating mechanisms of these molecules. However, most of the previous mechanistic understanding of CLC channels came from electrophysiological studies of a branch of the channel family, the muscle-type CLC channels in vertebrate species. These vertebrate CLC channels were predicted to contain two identical but independent pores, and this hypothesis was confirmed by the solved bacterial CLC structures. The opening and closing of the vertebrate CLC channels are also known to couple to the permeant ions via their binding sites in the ion-permeation pathway. The bacterial CLC structures can probably serve as a structural model to explain the gating-permeation coupling mechanism. However, the CLC-ec1 protein in E. coli was most recently shown to be a Cl-H+ antiporter, but not an ion channel. The molecular basis to explain the difference between vertebrate and bacterial CLCs, especially the distinction between an ion channel and a transporter, remains a challenge in the structure/function studies for the CLC family.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.67.032003.153012
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    THE PLASTIC HUMAN BRAIN CORTEX (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 28 (2005), S. 377-401 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Plasticity is an intrinsic property of the human brain and represents evolution's invention to enable the nervous system to escape the restrictions of its own genome and thus adapt to environmental pressures, physiologic changes, and experiences. Dynamic shifts in the strength of preexisting connections across distributed neural networks, changes in task-related cortico-cortical and cortico-subcortical coherence and modifications of the mapping between behavior and neural activity take place in response to changes in afferent input or efferent demand. Such rapid, ongoing changes may be followed by the establishment of new connections through dendritic growth and arborization. However, they harbor the danger that the evolving pattern of neural activation may in itself lead to abnormal behavior. Plasticity is the mechanism for development and learning, as much as a cause of pathology. The challenge we face is to learn enough about the mechanisms of plasticity to modulate them to achieve the best behavioral outcome for a given subject.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144216
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    QUANTUM DOTS AS CELLULAR PROBES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 55-76 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Robust and bright light emitters, semiconductor nanocrystals [quantum dots (QDs)] have been adopted as a new class of fluorescent labels. Six years after the first experiments of their uses in biological applications, there have been dramatic improvements in understanding surface chemistry, biocompatibility, and targeting specificity. Many studies have shown the great potential of using quantum dots as new probes in vitro and in vivo. This review summarizes the recent advances of quantum dot usage at the cellular level, including immunolabeling, cell tracking, in situ hybridization, FRET, in vivo imaging, and other related technologies. Limitations and potential future uses of quantum dot probes are also discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.7.060804.100432
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    INSTRUMENTATION ASPECTS OF ANIMAL PET (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 255-285 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Biological research has been accelerated by the development of noninvasive imaging techniques and by use of genetically engineered mice to model human diseases and normal development. Because these mice can be expensive, noninvasive imaging techniques, such as high-resolution positron emission tomography (PET), that permit longitudinal studies of the same animals are very attractive. Such studies reduce the number of animals used, reduce intersubject variability, and improve the accuracy of biological models. PET provides quantitative measurements of the spatiotemporal distribution of radiotracers and is an extremely powerful tool in using molecular imaging to study biology, to monitor disease intervention, and to establish pharmacokinetics for new drugs. The design of animal PET scanners has improved significantly in the past decade and can provide adequate image resolution and sensitivity to study transgenic mice. This article reviews the fundamental and technical challenges of small-animal PET imaging, with a particular focus on the latest developments and future directions of detector technologies and system design.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140021
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    DETERMINISTIC AND STOCHASTIC ELEMENTS OF AXONAL GUIDANCE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 187-221 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: An enormous literature has been developed on investigations of the growth and guidance of axons during development and after injury. In this review, we provide a guide to this literature as a resource for biomedical investigators. We first review briefly the molecular biology that is known to regulate migration of the growth cone and branching of axonal arbors. We then outline some important fundamental considerations that are important to the modeling of the phenomenology of these guidance effects and of what is known of their underlying internal mechanisms. We conclude by providing some thoughts on the outlook for future biomedical modeling in the field.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.7.060804.100446
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    BIOCHEMISTRY AND BIOMECHANICS OF CELL MOTILITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 105-150 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Cell motility is an essential cellular process for a variety of biological events. The process of cell migration requires the integration and coordination of complex biochemical and biomechanical signals. The protrusion force at the leading edge of a cell is generated by the cytoskeleton, and this force generation is controlled by multiple signaling cascades. The formation of new adhesions at the front and the release of adhesions at the rear involve the outside-in and inside-out signaling mediated by integrins and other adhesion receptors. The traction force generated by the cell on the extracellular matrix (ECM) regulates cell-ECM adhesions, and the counter force exerted by ECM on the cell drives the migration. The polarity of cell migration can be amplified and maintained by the feedback loop between the cytoskeleton and cell-ECM adhesions. Cell migration in three-dimensional ECM has characteristics distinct from that on two-dimensional ECM. The migration of cells is initiated and modulated by external chemical and mechanical factors, such as chemoattractants and the mechanical forces acting on the cells and ECM, as well as the surface density, distribution, topography, and rigidity of the ECM.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.7.060804.100340
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