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  • Articles  (19,522)
  • Articles: DFG German National Licenses  (19,522)
  • Annual Reviews  (19,522)
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  • 1
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 117-142 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract The enteric nervous system exerts local control over mixing and propulsive movements in the small intestine. When digestion is in progress, intrinsic primary afferent neurons (IPANs) are activated by the contents of the intestine. The IPANs that have been physiologically characterized are in the intrinsic myenteric ganglia. They are numerous, about 650/mm length of small intestine in the guinea pig, and communicate with each other through slow excitatory transmission to form self-reinforcing assemblies. High proportions of these neurons respond to chemicals in the lumen or to tension in the muscle; physiological stimuli activate assemblies of hundreds or thousands of IPANs. The IPANs make direct connections with muscle motor neurons and with ascending and descending interneurons. The circular muscle contracts as an annulus, about 2-3 mm in minimum oral-to-anal extent in the guinea pig small intestine. The smooth muscle cells form an electrical syncytium that is innervated by about 300 excitatory and 400 inhibitory motor neurons per mm length. The intrinsic nerve circuits that control mixing and propulsion in the small intestine are now known, but it remains to be determined how they are programmed to generate the motility patterns that are observed.
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  • 2
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 209-226 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 3
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 249-265 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 4
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 289-304 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 5
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 54 (1992), S. 601-618 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 6
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 283-310 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Intercellular channels present in gap junctions allow cells to share small molecules and thus coordinate a wide range of behaviors. Remarkably, although junctions provide similar functions in all multicellular organisms, vertebrates and invertebrates use unrelated gene families to encode these channels. The recent identification of the invertebrate innexin family opens up powerful genetic systems to studies of intercellular communication. At the same time, new information on the physiological roles of vertebrate connexins has emerged from genetic studies. Mutations in connexin genes underlie a variety of human diseases, including deafness, demyelinating neuropathies, and lens cataracts. In addition, gene targeting of connexins in mice has provided new insights into connexin function and the significance of connexin diversity.
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  • 7
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 54 (1992), S. 799-826 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 8
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 571-573 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 9
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 54 (1992), S. 885-909 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 10
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 17-54 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 11
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 337-362 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. By cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the receptors for sulfonylureas (SUR1 and SUR2), researchers have clarified the molecular structure of KATP channels. KATP channels comprise two subunits: a Kir6.0 subfamily subunit, which is a member of the inwardly rectifying K+ channel family; and a SUR subunit, which is a member of the ATP-binding cassette (ABC) protein superfamily. KATP channels are the first example of a heteromultimeric complex assembled with a K+ channel and a receptor that are structurally unrelated to each other. Since 1995, molecular biological and molecular genetic studies of KATP channels have provided insights into the structure-function relationships, molecular regulation, and pathophysiological roles of KATP channels.
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  • 12
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 391-415 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.
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  • 13
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 417-433 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract The acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. Although the maturation of sexual function and reproduction occurs after birth, essentially all of the critical developmental steps take place during embryogenesis. Temporally, these steps can be divided into two different phases: sex determination, the initial event that determines whether the gonads will develop as testes or ovaries; and sexual differentiation, the subsequent events that ultimately produce either the male or the female sexual phenotype. A basic tenet of sexual development in mammals is that genetic sex-determined by the presence or absence of the Y chromosome-directs the embryonic gonads to differentiate into either testes or ovaries. Thereafter, hormones produced by the testes direct the developmental program leading to male sexual differentiation. In the absence of testicular hormones, the pathway of sexual differentiation is female. This chapter reviews the anatomic and cellular changes that constitute sexual differentiation and discusses SRY and other genes, including SF-1, WT1, DAX-1, and SOX9, that play key developmental roles in this process. Dose-dependent interactions among these genes are critical for sex determination and differentiation.
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  • 14
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 237-272 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 15
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 297-319 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 16
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 349-369 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 17
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 399-417 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 18
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 661-681 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 19
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 55 (1993), S. 785-817 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 20
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 649-669 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 21
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 671-689 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 22
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 711-739 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 23
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 741-761 
    ISSN: 0066-4278
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  • 24
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 763-796 
    ISSN: 0066-4278
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  • 25
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 371-397 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 26
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 61 (1999), S. 683-697 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Vasopressin or AVP regulates water reabsorption by the kidney inner medullary collecting duct (IMCD) through the insertion and removal of aquaporin (AQP) 2 water channels into the IMCD apical membrane. AVP-elicited trafficking of AQP2 with the apical membrane occurs via a specialized population of vesicles that resemble synaptic vesicles in neurons. AQP2 vesicles and the IMCD apical membrane contain homologs of vesicle-targeting and signal transduction proteins found in neurons. Expression studies of AQP2, including human AQP2 mutants, suggest that the carboxyl-terminal domain of AQP2 is important in AQP2 trafficking, particularly as a site for cAMP-dependent protein kinase phosphorylation. These present data reveal that IMCD cells possess a complex integrated-signaling and vesicle-trafficking machinery that provides integration of AVP-elicited water transport with many other parameters within the IMCD cell as well as kidney.
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  • 27
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 219-244 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 28
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 691-709 
    ISSN: 0066-4278
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  • 29
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 797-810 
    ISSN: 0066-4278
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  • 30
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 56 (1994), S. 811-829 
    ISSN: 0066-4278
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  • 31
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 355-385 
    ISSN: 0066-4278
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  • 32
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 115-134 
    ISSN: 0066-4278
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  • 33
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 151-170 
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  • 34
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 547-564 
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  • 35
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 62 (2000), S. 25-50 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Ventricular fibrillation (VF) is the major immediate cause of sudden cardiac death. Traditionally, VF has been defined as turbulent cardiac electrical activity, which implies a large amount of irregularity in the electrical waves that underlie ventricular excitation. During VF, the heart rate is too high (〉 550 excitations/minute) to allow adequate pumping of blood. In the electrocardiogram (ECG), ventricular complexes that are ever-changing in frequency, contour, and amplitude characterize VF. This article reviews prevailing theories for the initiation and maintenance of VF, as well as its spatio-temporal organization. Particular attention is given to recent experiments and computer simulations suggesting that VF may be explained in terms of highly periodic three-dimensional rotors that activate the ventricles at exceedingly high frequency. Such rotors may show at least two different behaviors: (a) At one extreme, they may drift throughout the heart at high speeds producing beat-to-beat changes in the activation sequence. (b) At the other extreme, rotors may be relatively stationary, activating the ventricles at such high frequencies that the wave fronts emanating from them breakup at varying distances, resulting in complex spatio-temporal patterns of fibrillatory conduction. In either case, the recorded ECG patterns are indistinguishable from VF. The data discussed have paved the way for a better understanding of the mechanisms of VF in the normal, as well as the diseased, human heart. When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them ... If the heart trembles, has little power and sinks, the disease is advancing and death is near. Ebers Papyrus ~3500 BC
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  • 36
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 791-804 
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  • 37
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 805-826 
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  • 38
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 57 (1995), S. 827-872 
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  • 39
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 1-19 
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  • 40
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 62 (2000), S. 179-205 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract We use a comparative approach to examine some of the physiological traits that make flight possible. Comparisons of related fliers and runners suggest that fliers generally have higher aerobic metabolic capacities than runners but that the difference is highly dependent on the taxa studied. The high metabolic rates of fliers relative to runners, especially in insects, are correlated with high locomotory muscle cycle frequencies and low efficiences of conversion of metabolic power to mechanical power. We examine some factors that produce variation in flight respiration and energetics. Air temperature strongly affects the flight metabolic rate of some insects and birds. Flight speed interacts with flier mass, so that small fliers tend to exhibit a Jshaped power curve and larger fliers a U-shaped power curve. As body size increases, mass-specific aerobic flight metabolism decreases in most studies, but mass-specific power output is constant or increases, leading to an increase in efficiency with size. Intraspecific studies have revealed specific genetically based effects on flight metabolism and power output and multiple ecological correlates of flight capabilities.
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  • 41
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 93-113 
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  • 42
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 73-92 
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  • 43
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 115 
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  • 44
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 209-229 
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  • 45
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 253-273 
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 329-348 
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 275-297 
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 349-362 
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 58 (1996), S. 483-507 
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 62 (2000), S. 439-466 
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    Notes: Abstract Thyroid hormone is essential for normal development, differentiation, and metabolic balance. Thyroid hormone action is mediated by multiple thyroid hormone receptor isoforms derived from two distinct genes. The thyroid hormone receptors belong to a nuclear receptor superfamily that also includes receptors for other small lipophilic hormones. Thyroid hormone receptors function by binding to specific thyroid hormone-responsive sequences in promoters of target genes and by regulating transcription. Thyroid hormone receptors often form heterodimers with retinoid X receptors. Heterodimerization is regulated through distinct mechanisms that together determine the specificity and flexibility of the sequence recognition. Amino-terminal regions appear to modulate thyroid hormone receptor function in an isoform-dependent manner. Unliganded thyroid hormone receptor represses transcription through recruitment of a corepressor complex, which also includes Sin3A and histone deacetylase. Ligand binding alters the conformation of the thyroid hormone receptor in such a way as to release the corepressor complex and recruit a coactivator complex that includes multiple histone acetyltransferases, including a steroid receptor family coactivator, p300/CREB-binding protein-associated factor (PCAF), and CREB binding protein (CBP). The existence of histone-modifying activities in the transcriptional regulatory complexes indicates an important role of chromatin structure. Stoichiometric, structural, and sequence-specific rules for coregulator interaction are beginning to be understood, as are aspects of the tissue specificity of hormone action. Moreover, knockout studies suggest that the products of two thyroid hormone receptor genes mediate distinct functions in vivo. The increased understanding of the structure and function of thyroid hormone receptors and their interacting proteins has markedly clarified the molecular mechanisms of thyroid hormone action.
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    Annual Review of Physiology 62 (2000), S. 535-572 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    Notes: Abstract Chloride secretion is the major determinant of mucosal hydration thoughout the gastrointestinal tract, and chloride transport is also pivotal in the regulation of fluid secretion by organs that drain into the intestine. Moreover, there are pathological consequences if chloride secretion is either reduced or increased such as in cystic fibrosis and secretory diarrhea, respectively. With the molecular cloning of many of the proteins and regulatory factors that make up the chloride secretory mechanism, there have been significant advances in our understanding of this process at the cellular level. Similarly, emerging data have clarified the intercellular relationships that govern the extent of chloride secretion. The goal of our article is to review this area of investigation, with an emphasis on recent developments and their implications for the physiology and pathophysiology of chloride transport.
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 62 (2000), S. 595-620 
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    Notes: Abstract Epithelial tissues such as kidney, lung, and breast arise through branching morphogenesis of a pre-existing epithelial structure. They share common morphological stages and a need for regulation of a similar set of developmental decisions-where to start; when, where, and in which direction to branch; and how many times to branch-decisions requiring regulation of cell proliferation, apoptosis, invasiveness, and cell motility. It is likely that similar molecular mechanisms exist for the epithelial branching program. Here we focus on the development of the collecting system of the kidney, where, from recent data using embryonic organ culture, cell culture models of branching morphogenesis, and targeted gene deletion experiments, the outlines of a working model for branching morphogenesis begin to emerge. Key branching morphogenetic molecules in this model include growth factors, transcription factors, distal effector molecules (such as extracellular matrix proteins, integrins, proteinases and their inhibitors), and genes regulating apoptosis and cell proliferation.
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    Annual Review of Physiology 62 (2000), S. 723-753 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    Notes: Abstract Motor systems can adapt rapidly to changes in external conditions and to switching of internal goals. They can also adapt slowly in response to training, alterations in the mechanics of the system, and any changes in the system resulting from injury. This article reviews the mechanisms underlying short- and long-term adaptation in rhythmic motor systems. The neuronal networks underlying the generation of rhythmic motor patterns (central pattern generators; CPGs) are extremely flexible. Neuromodulators, central commands, and afferent signals all influence the pattern produced by a CPG by altering the cellular and synaptic properties of individual neurons and the coupling between different populations of neurons. This flexibility allows the generation of a variety of motor patterns appropriate for the mechanical requirements of different forms of a behavior. The matching of motor output to mechanical requirements depends on the capacity of pattern-generating networks to adapt to slow changes in body mechanics and persistent errors in performance. Afferent feedback from body and limb proprioceptors likely plays an important role in driving these long-term adaptive processes.
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    Annual Review of Physiology 62 (2000), S. 755-778 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    Notes: Abstract In recent years, it has become apparent that ligand-gated ion channels (ionotropic receptors) in the neuronal plasma membrane interact via their cytoplasmic domains with a multitude of intracellular proteins. Different classes of ligand-gated channels associate with distinct sets of intracellular proteins, often through specialized scaffold proteins containing PDZ domains. These specific interactions link the receptor channel to the cortical cytoskeleton and to appropriate signal transduction pathways in the cell. Thus ionotropic receptors are components of extensive protein complexes that are likely involved in the subcellular targeting, cytoskeletal anchoring, and localized clustering of the receptors at specific sites on the neuronal surface. In addition to structural functions, receptor-associated proteins can play important roles as activity modulators or downstream effectors of ligand-gated channels.
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    Annual Review of Physiology 62 (2000), S. 825-846 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    Notes: Abstract Mortality of infants of 〈1-kg birth weight has decreased because of surfactant treatments, antenatal glucocorticoid treatments, and new ventilation strategies. However, many of these infants develop a chronic lung disease characterized by an arrest of lung development and interference with alveolarization. Antenatal glucocorticoids can induce early lung maturation clinically, but new information from transgenic and other experimental models indicates that traditional explanations for glucocorticoid effects on the developing lung are inadequate. These very preterm infants have lungs with small lung gas volumes and delicate lung tissue that are susceptible to injury with the initiation of ventilation and subsequent ventilation. Antenatal proinflammatory exposures are frequent in very preterm infants, and postnatal injury is associated with elevations of proinflammatory cytokines in the lungs. One hypothesis is that proinflammatory cytokines can promote or interfere with lung development as well as promote lung injury. Mechanisms of lung injury being characterized in the adult lung may have unique characteristics in the developing lung.
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    Annual Review of Physiology 63 (2001), S. 1-14 
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    Annual Review of Physiology 63 (2001), S. 99-117 
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    Notes: Abstract In order to control cell functions, hormones and neurotransmitters generate an amazing diversity of Ca2+ signals such as local and global Ca2+ elevations and also Ca2+ oscillations. In pancreatic acinar cells, cholecystokinin (CCK) stimulates secretion of digestive enzyme and promotes cell growth, whereas acetylcholine (ACh) essentially triggers enzyme secretion. Pancreatic acinar cells are a classic model for the study of CCK- and ACh-evoked specific Ca2+ signals. In addition to inositol 1,4,5 trisphosphate (IP3), recent studies have shown that cyclic ADPribose (cADPr) and nicotinic acid adenine dinucleotide phosphate (NAADP) release Ca2+ in pancreatic acinar cells. Moreover, it has also been shown that both ACh and CCK trigger Ca2+ spikes by co-activation of IP3 and ryanodine receptors but by different means. ACh uses IP3 and Ca2+, whereas CCK uses cADPr and NAADP. In addition, CCK activates phospholipase A2 and D. The concept emerging from these studies is that agonist-specific Ca2+ signals in a single target cell are generated by combination of different intracellular messengers.
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    Annual Review of Physiology 63 (2001), S. 141-164 
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    Notes: Abstract The traditionally accepted theory has been that most of the biological effects of growth hormone (GH) are mediated by circulating (endocrine) insulin-like growth factor-I (IGF-I). This dogma was modified when it was discovered that most tissues express IGF-I that can act via an autocrine/paracrine fashion. In addition, both GH and IGF-I had independent effects on various target tissues. Using tissue-specific gene deletion of IGF-I in the liver, it has been shown that circulating IGF-I is predominantly liver-derived but is not essential for normal postnatal growth. Therefore, it is proposed that non-hepatic tissue-derived IGF-I may be sufficient for growth and development. Thus the original somatomedin hypothesis has undergone further modifications.
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    Annual Review of Physiology 63 (2001), S. 215-233 
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    Notes: Abstract During the 1980s the purification, cloning, and expression of various forms of guanylyl cyclase (GC) revealed that they served as receptors for extracellular signals. Seven membrane forms, which presumably exist as homodimers, and four subunits of apparent heterodimers (commonly referred to as the soluble forms) are known, but in animals such as nematodes, much larger numbers of GCs are expressed. The number of transmembrane segments (none, one, or multiple) divide the GC family into three groups. Those with no or one transmembrane segment bind nitric oxide/carbon monoxide (NO/CO) or peptides. There are no known ligands for the multiple transmembrane segment class of GCs. Mutational and structural analyses support a model where catalysis requires a shared substrate binding site between the subunits, whether homomeric or heteromeric in nature. Because some cyclases or cyclase ligand genes lack specific GC inhibitors, disruption of either has been used to define the functions of individual cyclases, as well as to define human genetic disease counterparts.
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    Annual Review of Physiology 63 (2001), S. 235-257 
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    Notes: Abstract Ionic currents activated by hyperpolarization and regulated by cyclic nucleotides were first discovered more than 20 years ago. Recently the molecular identity of the underlying channels has been unveiled. The structural features of the protein sequences are discussed and related to the mechanisms of activation, selectivity for cyclic nucleotides, and ion permeation. Coverage includes a comparison of the biophysical properties of recombinant and native channels and their significance for the physiological functions of these channels.
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    Annual Review of Physiology 63 (2001), S. 119-139 
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    Notes: Abstract Gastric epithelial organization and function are controlled and maintained by a variety of endocrine and paracrine mediators. Peptides encoded by the gastrin gene are an important part of this system because targeted deletion of the gene, or of the gastrin-CCKB receptor gene, leads to decreased numbers of parietal cells and decreased gastric acid secretion. Recent studies indicate that the gastrin precursor, preprogastrin, gives rise to a variety of products, each with a distinctive spectrum of biological activity. The conversion of progastrin to smaller peptides is regulated by multiple mechanisms including prohormone phosphorylation and secretory vesicle pH. Progastrin itself stimulates colonic epithelial proliferation; biosynthetic intermediates (Gly-gastrins) stimulate colonic epithelial proliferation and gastric epithelial differentiation; and C-terminally amidated gastrins stimulate colonic proliferation, gastric epithelial proliferation and differentiation, and acid secretion. The effects of progastrin-derived peptides on gastric epithelial function are mediated in part by release of paracrine factors that include histamine, epidermal growth factor (EGF)-receptor ligands, and Reg. The importance of the appropriate regulation of this system is shown by the observation that prolonged moderate hypergastrinemia in transgenic mice leads to remodelling of the gastric epithelium, and in the presence of Helicobacter, to gastric cancer.
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    Annual Review of Physiology 63 (2001), S. 165-192 
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    Notes: Abstract There was a time when the classification of sex hormones was simple. Androgens were male and estrogens female. What remains true today is that in young adults androgen levels are higher in males and estrogen levels higher in females. More recently we have learned that estrogens are necessary in males for regulation of male sexual behavior, maintenance of the skeleton and the cardiovascular system, and for normal function of the testis and prostate. The importance of androgen in females was never in doubt, it is after all the precursor of estrogen as the substrate for aromatase, the enzyme that produces estrogen. In addition, the tissue distribution of androgen receptors suggests that androgens themselves are important in the ovary, uterus, breast, and brain. New information promises to clarify some of the complex issues of the physiological roles of estrogen and the contribution of estrogen to the development of neoplastic diseases in humans. The discovery of the second estrogen receptor, the creation of mutant mice defective in both estrogen receptors and in the aromatase gene, the solution of the structures of the ligand-binding domains of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), the finding of novel routes through which estrogen receptors can modulate transcription, and the identification of a man with a bi-allelic disruptive mutation of the ERalpha gene are but some of the milestones. This review focuses on the mechanistic aspects of signal transduction mediated by ERs and on the physiological consequences of deficiency of estrogen or estrogen receptor in the available mouse models.
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    Annual Review of Physiology 59 (1997), S. 573-574 
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    Annual Review of Physiology 59 (1997), S. 575-599 
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    Notes: Abstract Physical forces of gravity, hemodynamic stresses, and movement play a critical role in tissue development. Yet, little is known about how cells convert these mechanical signals into a chemical response. This review attempts to place the potential molecular mediators of mechanotransduction (e.g. stretch-sensitive ion channels, signaling mollecules, cytoskeleton, integrins) within the context of the structural complexity of living cells. The model presented relies on recent experimental findings, which suggests that cells use tensegrity architecture for their organization. Tensegrity predicts that cells are hard-wired to respond immediately to mechanical stresses transmitted over cell surface receptors that physically couple the cytoskeleton to extracellular matrix (e.g. integrins) or to other cells (cadherins, selectins, CAMs). Many signal transducing molecules that are activated by cell binding to growth factors and extracellular matrix associate with cytoskeletal scaffolds within focal adhesion complexes. Mechanical signals, therefore, may be integrated with other environmental signals and transduced into a biochemical response through force-dependent changes in scaffold geometry or molecular mechanics. Tensegrity also provides a mechanism to focus mechanical energy on molecular transducers and to orchestrate and tune the cellular response.
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    Annual Review of Physiology 63 (2001), S. 359-390 
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    Notes: Abstract Marine teleosts at high latitudes can encounter ice-laden seawater that is approximately 1oC colder than the colligative freezing point of their body fluids. They avoid freezing by producing small antifreeze proteins (AFPs) that adsorb to ice and halt its growth, thereby producing an additional non-colligative lowering of the freezing point. AFPs are typically secreted by the liver into the blood. Recently, however, it has become clear that AFP isoforms are produced in the epidermis (skin, scales, fin, and gills) and may serve as a first line of defense against ice propagation into the fish. The basis for the adsorption of AFPs to ice is something of a mystery and is complicated by the extreme structural diversity of the five antifreeze types. Despite the recent acquisition of several AFP three-dimensional structures and the definition of their ice-binding sites by mutagenesis, no common ice-binding motif or even theme is apparent except that surface-surface complementarity is important for binding. The remarkable diversity of antifreeze types and their seemingly haphazard phylogenetic distribution suggest that these proteins might have evolved recently in response to sea level glaciation occurring just 1-2 million years ago in the northern hemisphere and 10-30 million years ago around Antarctica. Not surprisingly, the expression of AFP genes from different origins can also be quite dissimilar. The most intensively studied system is that of the winter flounder, which has a built-in annual cycle of antifreeze expression controlled by growth hormone (GH) release from the pituitary in tune with seasonal cues. The signal transduction pathway, transcription factors, and promoter elements involved in this process are just beginning to be characterized.
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    Annual Review of Physiology 63 (2001), S. 471-494 
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    Notes: Abstract There is increasing evidence suggesting that formation of the tracheobronchial tree and alveoli results from heterogeneity of the epithelial-mesenchymal interactions along the developing respiratory tract. Recent genetic data support this idea and show that this heterogeneity is likely the result of activation of distinct networks of signaling molecules along the proximal-distal axis. Among these signals, fibroblast growth factors, retinoids, Sonic hedgehog, and transforming growth factors appear to play prominent roles. We discuss how these and other pattern regulators may be involved in initiation, branching, and differentiation of the respiratory system.
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    Annual Review of Physiology 5 (1943), S. 207-228 
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    Annual Review of Physiology 5 (1943), S. 229-252 
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    Annual Review of Physiology 5 (1943), S. 321-344 
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    Annual Review of Physiology 5 (1943), S. 1-16 
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    Annual Review of Physiology 59 (1997), S. 633-657 
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    Notes: Abstract Although mechanosensory responses are ubiquitous and diverse, the molecular bases of mechanosensation in most cases remain mysterious.MscL, a mechano-sensitive channel of large conductance of Escherichia coli and its bacterial homologues are the first and currently only channel molecules shown to directly sense mechanical stretch of the membrane. In response to the tension conveyed via the lipid bilayer, MscL increases its open probability by several orders of magnitude. In the present review we describe the identification, cloning, and first sets of biophysical and structural data on this simplest mechanosensory molecule. We discovered a 2.5-ns mechanosensitive conductance in giant E. coli spheroplasts. Using chromatographies to enrich the target and patch clamp to assay the channel activity in liposome-reconstituted fractions, we identified the MscL protein and cloned the mscL gene. MscL comprises 136 amino acid residues (15 kDa), with two highly hydrophobic regions, and resides in the inner membrane of the bacterium. PhoA-fusion experiments indicate that the protein spans the membrane twice with both termini in the cytoplasm. Spectroscopic techniques show that it is highly helical. Expression of MscL tandems and covalent cross-linking suggest that the active channel complex is a homo-hexamer. We have identified several residues, which when deleted or substituted, affect channel kinetics or mechanosensitivity. Although unique when discovered, highly conserved MscL homologues in both gram-negative and gram-positive bacteria have been found, suggesting their ubiquitous importance among bacteria.
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    Annual Review of Physiology 5 (1943), S. 63-78 
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    Annual Review of Physiology 5 (1943), S. 105-122 
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    Annual Review of Physiology 5 (1943), S. 133-156 
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    Annual Review of Physiology 5 (1943), S. 253-274 
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    Annual Review of Physiology 5 (1943), S. 181-206 
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    Annual Review of Physiology 5 (1943), S. 275-294 
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    Annual Review of Physiology 64 (2002), S. 407-429 
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    Notes: Abstract Recent discoveries have revolutionized our conceptions of enzyme-substrate specificity in signal transduction pathways. Protein kinases A and C are localized to discreet subcellular regions, and this localization changes in an isozyme-specific manner upon activation, a process referred to as translocation. The mechanisms for translocation involve interactions of soluble kinases with membrane-bound anchor proteins that recognize individual kinase isoenzymes and their state of activation. Recently, modulation of kinase-anchor protein interactions has been used to specifically regulate, positively or negatively, the activity of C kinase isozymes. Also described in this review is a role for the Rab family of small G proteins in regulating subcellular protein trafficking. The pathophysiological significance of disrupted subcellular protein transport in cell signaling and the potential therapeutic utility of targeted regulation of these events are in the process of being characterized.
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    Annual Review of Physiology 64 (2002), S. 1-18 
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    Notes: This article gives a history of the evidence (a) that animal cell membranes contain pumps that expel sodium ions in exchange for potassium ions; (b) that the pump derives energy from the hydrolysis of ATP; (c) that it is thermodynamically reversible-artificially steep transmembrane ion gradients make it run backward synthesizing ATP from ADP and orthophosphate; (d) that its mechanism is a ping-pong one, in which phosphorylation of the pump by ATP is associated with an efflux of three sodium ions, and hydrolysis of the phosphoenzyme is associated with an influx of two potassium ions; (e) that each half of the working cycle involves both the transfer of a phosphate group and a conformational change-the phosphate transfer being associated with the occlusion of ions bound at one surface and the conformational change releasing the occluded ions at the opposite surface.
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    Annual Review of Physiology 63 (2001), S. 871-894 
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    Notes: Abstract A variety of isoforms of mammalian voltage-gated sodium channels have been described. Ten genes encoding sodium channel alpha subunits have been identified, and nine of those isoforms have been functionally expressed in exogenous systems. The alpha subunit is associated with accessory beta subunits in some tissues, and three genes encoding different beta subunits have been identified. The alpha subunit isoforms have distinct patterns of development and localization in the nervous system, skeletal and cardiac muscle. In addition, many of the isoforms demonstrate subtle differences in their functional properties. However, there are no clear subfamilies of the channels, unlike the situation with potassium and calcium channels. The subtle differences in the functional properties of the sodium channel isoforms result in unique conductances in specific cell types, which have important physiological effects for the organism. Small alterations in the electrophysiological properties of the channel resulting from mutations in specific isoforms cause human diseases such as periodic paralysis, long QT syndrome, and epilepsy.
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    Annual Review of Physiology 64 (2002), S. 635-661 
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    Notes: Abstract Bile salts are the major organic solutes in bile and undergo extensive enterohepatic circulation. Hepatocellular bile salt uptake is mediated predominantly by the Na+-taurocholate cotransport proteins Ntcp (rodents) and NTCP (humans) and by the Na+-independent organic anion-transporting polypeptides Oatp1, Oatp2, and Oatp4 (rodents) and OATP-C (humans). After diffusion (bound by intracellular bile salt-binding proteins) to the canalicular membrane, monoanionic bile salts are secreted into bile canaliculi by the bile salt export pump Bsep (rodents) or BSEP (humans). Both belong to the ATP-binding cassette (ABC) transporter superfamily. Dianionic conjugated bile salts are secreted into bile by the multidrug-resistance-associated proteins Mrp2/MRP2. In bile ductules, a minor portion of protonated bile acids and monomeric bile salts are reabsorbed by non-ionic diffusion and the apical sodium-dependent bile salt transporter Asbt/ASBT, transported back into the periductular capillary plexus by Mrp3/MRP3 [and/or a truncated form of Asbt (tAsbt)], and subjected to cholehepatic shunting. The major portion of biliary bile salts is aggregated into mixed micelles and transported into the intestine, where they are reabsorbed by apical Oatp3, the apical sodium-dependent bile salt transporter (ASBT), cytosolic intestinal bile acid-binding protein (IBABP), and basolateral Mrp3/MRP3 and tAsbt. Transcriptional and posttranscriptional regulation of these enterohepatic bile salt transporters is closely related to the regulation of lipid and cholesterol homeostasis. Furthermore, defective expression and function of bile salt transporters have been recognized as important causes for various cholestatic liver diseases.
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    Annual Review of Physiology 60 (1998), S. 143-159 
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    Notes: Abstract The intercellular tight junction is the rate-limiting barrier in the paracellular pathway for permeation by ions and larger solutes. A variety of widely used electrical and flux approaches are used in the analyses of solute permeation through this pathway; however, each has limitations in practice. It is now clear that solute permeation across tight junctions is dynamically regulated by intracellular events with a common effector mechanism apparently tied to the cytoskeleton. These pathways, which regulate tight junction solute permeability, are targets that produce epithelial barrier dysfunction in a variety of disease states. However, regulation of solute permeation across the junctional barrier may also represent a potential means to improve bioavailability of orally administered bioactive solutes.
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    Annual Review of Physiology 60 (1998), S. 161-177 
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    Notes: Abstract The tight junction (TJ) is not randomly located on the cell membrane, but occupies a precise position at the outermost edge of the intercellular space and, therefore, is itself considered a polarized structure. This article reviews the most common experimental approaches for studying this relationship. We then discuss three main topics. (a) The mechanisms of polarization that operate regardless of the presence of TJs: We explore a variety of polarization mechanisms that operate at stages of the cell cycle in which TJs may be already established. (b) TJs and polarity as partners in highly dynamic processes: Polarity and TJs are steady state situations that may be drastically changed by a variety of signaling events. (c) Polarized distribution of membrane molecules that depend on TJs: This refers to molecules (mainly lipids) whose polarized distribution, although not the direct result of TJs, depends on these structures to maintain such distribution.
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    Annual Review of Physiology 60 (1998), S. 243-266 
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    Notes: Abstract This review focuses on sodium-independent transport systems for organic cations in small intestine, liver, kidney, and brain. The roles of P-glycoproteins (MDR) and anion transporters (OATP) in organic cation transport are reported, and two members of the new transporter family OCT are described. The OCT transporters belong to a superfamily that includes multidrug-resistance proteins, facilitative diffusion systems, and proton antiporters. They mediate electrogenic transport of small organic cations with different molecular structures, independently of sodium and proton gradients. The current knowledge of the distribution and functional properties of cloned cation transport systems and of cation transport measured in intact plasma membranes is used to postulate identical or homologous transporters in intestine, liver, kidney, and brain.
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    Annual Review of Physiology 60 (1998), S. 179-197 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Calcium and sodium absorption by the kidney normally proceed in parallel. However, a number of physiological, pharmacological, pathological, and genetic conditions dissociate this relation. In each instance, the dissociation can be traced to the distal convoluted tubule, where calcium and sodium transport are inversely related. Based on the identification of the relevant sodium transporters in these cells and on analysis of the mechanism of calcium transport, an explanation for this inverse relation can be developed. Apical membrane calcium entry is mediated by voltage-sensitive calcium channels that are activated upon membrane hyperpolarization. Basolateral calcium efflux is effected primarily by Na+/Ca2+ exchange. According to the model, inhibition of sodium entry through either the Na-Cl cotransporter or the Na+ channel hyperpolarizes the cell, as does parathyroid hormone, thereby activating the calcium entry channel and increasing the driving force for diffusional entry. Membrane hyperpolarization also increases the driving force of calcium efflux through the Na+/Ca2+ exchanger. Thus sodium-dependent changes of calcium transport are indirect and occur secondarily through effects on membrane voltage.
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    Annual Review of Physiology 60 (1998), S. 199-220 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Since the molecular identification of the first aquaporin in 1992, the number of proteins known to belong to this family has been rapidly increasing. These members may be separated into two subgroups based on gene structure, sequence homology, and function. Regulation of the water permeability of the collecting ducts of the kidney is essential for urinary concentration. Aquaporin-2 and -3, which are representative of these subgroups, are colocalized in the collecting ducts. Understanding these subgroups will elucidate the differences between aquaporin-2 and -3. Aquaporin-2 is a vasopressin-regulated water channel located in the apical membrane, and aquaporin-3 is a constitutive water channel located in the basolateral membrane. In contrast to aquaporin-3, which appears to be less well regulated, many studies have now identified multiple regulational mechanisms at the gene, protein, and cell levels for aquaporin-2, thus reflecting its physiological importance. Evidence of the participation of aquaporin-2 in the pathophysiology of water-balance disorders is accumulating.
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  • 87
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    Annual Review of Physiology 60 (1998), S. 221-242 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Despite the fact that prostaglandins (PGs) have low intrinsic permeabilities across the plasma membrane, they must cross it twice: first upon release from the cytosol into the blood, and again upon cellular uptake prior to oxidation. Until recently, there were no cloned carriers that transported PGs. PGT is a broadly-expressed, 12-membrane-spanning domain integral membrane protein. When heterologously expressed in HeLa cells or Xenopus oocytes, it catalyzes the rapid, specific, and high-affinity uptake of PGE2, PGF2alpha, PGD2, 8-iso-PGF2alpha, and thromboxane B2. Functional studies indicate that PGT transports its substrate as the charged anion. The PGT substrate specificity and inhibitor profile match remarkably well with earlier in situ studies on the metabolic clearance of PGs by rat lung. Because PGT expression is especially high in this tissue, it is likely that PGT mediates the membrane step in PG clearance by the pulmonary circulation. Evidence is presented that PGT may play additional roles in other tissues and that there may be additional PG transporters yet to be identified molecularly.
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  • 88
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    Annual Review of Physiology 60 (1998), S. 267-286 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract The discovery in the chick embryo that a specific region of the neural crest, termed the cardiac neural crest, is essential for septation of the cardiac outflow tract and for aortic arch artery development has led to the classification of a whole series of human cardiac defects as neural crest-associated. Recently, several mouse genetic models have been effectively employed to yield new insights into the relationship between cardiac neural crest and structural heart development. In all the animal models of neural crest-related heart defects, prenatal mortality is too high to be attributed to structural defects of the heart alone, and there are obvious signs of severe cardiac dysfunction. The evidence indicates that poor viability is from impaired cardiac excitation-contraction coupling and contractile function at the myocyte level. The continued study of experimental and genetically defined models with neural crest-associated heart defects will prove useful in identifying the common pathways by which the neural crest contributes to normal heart development.
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    Annual Review of Physiology 60 (1998), S. 287-308 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Recent discoveries have led to a greater appreciation of the diverse mechanisms that underlie cardiac morphogenesis. Genetic strategies (primarily gene targeting approaches in mice) have significantly broadened research in cardiovascular developmental biology by illuminating new pathways involved in heart development and by allowing the genetic evaluation of pathways that have previously been implicated in these events. Advances have also been made using biochemical and cell- and tissue-based approaches. This review summarizes the author's interpretation of current trends in the effort to understand the molecular basis of cardiac development, with an emphasis on insights obtained from genetic models.
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 62 (2000), S. 947-950 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 91
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 62 (2000), S. 961-963 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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  • 92
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 65 (2003), S. 735-759 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract In Drosophila photoreceptors, the light-sensitive current is mediated downstream of phospholipase C by TRP (transient receptor potential) channels. Recent evidence suggests that Drosophila TRP channels are activated by diacylglycerol (DAG) or its metabolites (polyunsaturated fatty acids), possibly in combination with the reduction in phosphatidyl inositol 4,5 bisphosphate (PIP2). Consistent with this view, diacylglycerol kinase is identified as a key enzyme required for response termination. Signaling is critically dependent upon efficient PIP2 synthesis; mutants of this pathway in combination with genetically targeted PIP2 reporters provide unique insights into the kinetics and regulation of PIP2 turnover. Recent evidence indicates that a growing number of mammalian TRP homologues are also regulated by lipid messengers, including DAG, arachidonic acid, and PIP2.
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  • 93
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    Annual Review of Physiology 65 (2003), S. 701-734 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Maintenance of membrane lipid asymmetry is a dynamic process that influences many events over the lifespan of the cell. With few exceptions, most cells restrict the bulk of the aminophospholipids to the inner membrane leaflet by means of specific transporters. Working in concert with each other, these proteins correct for sporadic incursions of the aminophospholipids to the outer membrane leaflet as a result of bilayer imbalances created by various cellular events. A shift in the relative contribution in each of these activities can result in sustained exposure of the aminophospholipids at the cell surface, which allows capture of the cells by phagocytes before the integrity of the plasma membrane is compromised. The absence of an efficient recognition and elimination mechanism can result in uncontrolled and persistent presentation of self-antigens to the immune system, with development of autoimmune syndromes. To prevent this, phagocytes have developed a diverse array of distinct and redundant receptor systems that drive the postphagocytic events along pathways that facilitate cross-talk between the homeostatic and the immune systems. In this work, we review the basis for the proposed mechanism(s) by which apoptotic ligands appear on the target cell surface and the phagocyte receptors that recognize these moieties.
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    Annual Review of Physiology 65 (2003), S. 761-789 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Phosphoinositides [PPIs, which collectively refer to phosphorylated derivatives of phosphatidylinositol (PI)] have a pivotal role as precursors to important second messengers and as bona fide signaling and scaffold targeting molecules. This review focuses on recent advances that elucidate how PPIs, particularly PI(4,5)P2 (PIP2), directly regulate the actin cytoskeleton in vivo by modulating the activity and targeting of actin regulatory proteins. The role of PIP2 in stimulating actin polymerization and in establishing cytoskeleton-plasma membrane linkages is emphasized. In addition, the review presents tantalizing evidence that suggests how binding of selected cytoskeletal proteins to membrane PPIs may promote PPI clustering into raft lipid microdomains, alter their accessibility to other proteins, and even distort the bilayer conformation. These actions have profound implications for many other PPI-regulated membrane functions that are beginning to be uncovered, and they suggest how PPIs can mediate crosstalk between the actin cytoskeleton and an expanding spectrum of essential cellular functions.
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    Annual Review of Physiology 65 (2003), S. 851-879 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Rhodopsin is a retinal photoreceptor protein of bipartite structure consisting of the transmembrane protein opsin and a light-sensitive chromophore 11-cis-retinal, linked to opsin via a protonated Schiff base. Studies on rhodopsin have unveiled many structural and functional features that are common to a large and pharmacologically important group of proteins from the G protein-coupled receptor (GPCR) superfamily, of which rhodopsin is the best-studied member. In this work, we focus on structural features of rhodopsin as revealed by many biochemical and structural investigations. In particular, the high-resolution structure of bovine rhodopsin provides a template for understanding how GPCRs work. We describe the sensitivity and complexity of rhodopsin that lead to its important role in vision.
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    Annual Review of Physiology 66 (2004), S. 239-274 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although it is well established that during periods of torpor heterothermic mammals and birds can reduce metabolic rates (MR) substantially, the mechanisms causing the reduction of MR remain a controversial subject. The comparative analysis provided here suggests that MR reduction depends on patterns of torpor used, the state of torpor, and body mass. Daily heterotherms, which are species that enter daily torpor exclusively, appear to rely mostly on the fall of body temperature (Tb) for MR reduction, perhaps with the exception of very small species and at high torpor Tb, where some metabolic inhibition may be used. In contrast, hibernators (species capable of prolonged torpor bouts) rely extensively on metabolic inhibition, in addition to Tb effects, to reduce MR to a fraction of that observed in daily heterotherms. In small hibernators, metabolic inhibition and the large fall of Tb are employed to maximize energy conservation, whereas in large hibernators, metabolic inhibition appears to be employed to facilitate MR and Tb reduction at torpor onset. Over the ambient temperature (Ta) range where torpid heterotherms are thermo-conforming, the Tb-Ta differential is more or less constant despite a decline of MR with Ta; however, in thermo-regulating torpid individuals, the Tb-Ta differential is maintained by a proportional increase of MR as during normothermia, albeit at a lower Tb. Thermal conductance in most torpid thermo-regulating individuals is similar to that in normothermic individuals despite the substantially lower MR in the former. However, conductance is low when deeply torpid animals are thermo-conforming probably because of peripheral vasoconstriction.
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    Annual Review of Physiology 60 (1998), S. 407-429 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Gonadal hormones are known to act during development to establish permanent sex differences in the anatomy and function of the vertebrate brain. They also act on the adult brain to activate reproductive behaviors. However, there are wide gaps in our understanding of how sexually dimorphic neural circuits translate into sex differences in behavior and other CNS functions. Moreover, not all sexually dimorphic properties of the adult brain can be attributed to known effects of gonadal hormones during development or adulthood, and factors other than gonadal steroids may contribute to these sex differences. This paper reviews sexual differentiation and the role of gonadal steroids and non-gonadal factors on sexually dimorphic development of the avian brain.
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    Annual Review of Physiology 60 (1998), S. 497-523 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract In mammals the male sex determination switch is controlled by a single gene on the Y chromosome, SRY. SRY encodes a protein with an HMG-like DNA-binding domain, which probably acts as a local organizer of chromatin structure. It is believed to regulate downstream genes in the sex determination cascade, although no direct targets of SRY are clearly known. More genes in the pathway have been isolated through mutation approaches in mouse and human. At least three genes, SRY itself, SOX9, and DAX1, are dosage sensitive, providing molecular evidence that the sex determination step operates at a critical threshold. SRY initiates development of a testis from the bipotential cells of the early gonad. The dimorphic male and female pathways present a rare opportunity to link a pivotal gene in development with morphogenetic mechanisms that operate to pattern an organ and the differentiation of its cells. Mechanisms of testis organogenesis triggered downstream of SRY include pathways of cell signaling controlling cell reorganization, cell proliferation, cell migration, and vascularization.
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 60 (1998), S. 525-532 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    Annual Review of Physiology 60 (1998), S. 461-496 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract The luteinizing hormone receptor (LHR) is a member of the subfamily of glycoprotein hormone receptors within the superfamily of G protein-coupled receptor (GPCR)/seven-transmembrane domain receptors. Over the past eight years, major advances have been made in determining the structure and function of the LHR and its gene. The hormone-binding domain has been localized to exons 1-7 in the extracellular (EC) domain/region of the receptor, which contains several leucine-rich repeats. High-affinity binding of LH and human chorionic gonadotropin (hCG) causes secondary hormone or receptor contacts to be established with regions of the EC loop/transmembrane module that initiate signal transduction. Models of hormone-receptor interaction have been derived from the crystal structures of hCG and of the ribonuclease inhibitor, which also contains leucine-rich repeats. Such models provide a framework for the interpretation of mutational studies and for further experiments. The extracellular domain of the receptor has been overexpressed in vitro, which will facilitate crystallographic resolution of the structure of the receptor-binding site. The transmembrane domain/loop/cytoplasmic module transduces the signal for couplingto G proteins. Several constitutive, activating mutations that cause human disease have been found in helix VI and adjacent structures. These mutations have provided valuable information about mechanisms of signal transfer and G protein coupling. The structure of the LHR gene has been elucidated, and the regulation of its transcription is beginning to be understood. Valuable insights into receptor evolution have been derived from analysis of sequence homologies, the gene structure of glycoprotein hormone receptors and other members of the GPCR family, and the glycoprotein hormone receptor-like precursors identified in several invertebrate species.
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