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  • 1
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    The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel (2008)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2008-09-17
    Beschreibung: TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4). ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe(3+)-bound transferrin receptors, or after lysosomal degradation of ferritin-iron complexes and autophagic ingestion of iron-containing macromolecules, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe(2+) transporter known at present and it is highly expressed in erythroid precursors. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe(2+) transport protein. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe(2+) permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe(2+) at varying degrees, which correlate well with the disease severity. A comparison of TRPML1(-/- )ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe(2+) levels, an increase in intralysosomal Fe(2+) levels and an accumulation of lipofuscin-like molecules in TRPML1(-/-) cells. We propose that TRPML1 mediates a mechanism by which Fe(2+) is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301259/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Xian-Ping -- Cheng, Xiping -- Mills, Eric -- Delling, Markus -- Wang, Fudi -- Kurz, Tino -- Xu, Haoxing -- T32 HL007572/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):992-6. doi: 10.1038/nature07311. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Molecular, Cellular, and Developmental Biology, The University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794901" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cell Line ; Cell Membrane Permeability ; Endosomes/*metabolism ; Fibroblasts ; Fluorescence ; Humans ; Ion Transport ; Iron/analysis/*metabolism ; Lysosomes/*metabolism ; Mice ; Mucolipidoses/*metabolism ; Protons ; TRPM Cation Channels/deficiency/genetics/*metabolism ; Transfection ; Transient Receptor Potential Channels
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
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    Primary cilia are not calcium-responsive mechanosensors (2016)
    Springer Nature
    In: Nature
    Details
    Publikationsdatum: 2016-03-31
    Beschreibung: Primary cilia are not calcium-responsive mechanosensors Nature 531, 7596 (2016). doi:10.1038/nature17426 Authors: M. Delling, A. A. Indzhykulian, X. Liu, Y. Li, T. Xie, D. P. Corey & D. E. Clapham Primary cilia are solitary, generally non-motile, hair-like protrusions that extend from the surface of cells between cell divisions. Their antenna-like structure leads naturally to the assumption that they sense the surrounding environment, the most common hypothesis being sensation of mechanical force through calcium-permeable ion channels within the cilium. This Ca2+-responsive mechanosensor hypothesis for primary cilia has been invoked to explain a large range of biological responses, from control of left–right axis determination in embryonic development to adult progression of polycystic kidney disease and some cancers. Here we report the complete lack of mechanically induced calcium increases in primary cilia, in tissues upon which this hypothesis has been based. We developed a transgenic mouse, Arl13b–mCherry–GECO1.2, expressing a ratiometric genetically encoded calcium indicator in all primary cilia. We then measured responses to flow in primary cilia of cultured kidney epithelial cells, kidney thick ascending tubules, crown cells of the embryonic node, kinocilia of inner ear hair cells, and several cell lines. Cilia-specific Ca2+ influxes were not observed in physiological or even highly supraphysiological levels of fluid flow. We conclude that mechanosensation, if it originates in primary cilia, is not via calcium signalling.
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Springer Nature
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
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    Primary cilia are specialized calcium signalling organelles (2013)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2013-12-18
    Beschreibung: Primary cilia are solitary, non-motile extensions of the centriole found on nearly all nucleated eukaryotic cells between cell divisions. Only approximately 200-300 nm in diameter and a few micrometres long, they are separated from the cytoplasm by the ciliary neck and basal body. Often called sensory cilia, they are thought to receive chemical and mechanical stimuli and initiate specific cellular signal transduction pathways. When activated by a ligand, hedgehog pathway proteins, such as GLI2 and smoothened (SMO), translocate from the cell into the cilium. Mutations in primary ciliary proteins are associated with severe developmental defects. The ionic conditions, permeability of the primary cilia membrane, and effectiveness of the diffusion barriers between the cilia and cell body are unknown. Here we show that cilia are a unique calcium compartment regulated by a heteromeric TRP channel, PKD1L1-PKD2L1, in mice and humans. In contrast to the hypothesis that polycystin (PKD) channels initiate changes in ciliary calcium that are conducted into the cytoplasm, we show that changes in ciliary calcium concentration occur without substantially altering global cytoplasmic calcium. PKD1L1-PKD2L1 acts as a ciliary calcium channel controlling ciliary calcium concentration and thereby modifying SMO-activated GLI2 translocation and GLI1 expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112737/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delling, Markus -- DeCaen, Paul G -- Doerner, Julia F -- Febvay, Sebastien -- Clapham, David E -- P01 NS072040/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- P30-HD 18655/HD/NICHD NIH HHS/ -- T32-HL007572/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 12;504(7479):311-4. doi: 10.1038/nature12833.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, 320 Longwood Avenue, Boston, Massachusetts 02115, USA [2]. ; Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, 320 Longwood Avenue, Boston, Massachusetts 02115, USA. ; 1] Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, 320 Longwood Avenue, Boston, Massachusetts 02115, USA [2] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336288" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Calcium/metabolism ; Calcium Channels/chemistry/*metabolism ; *Calcium Signaling ; Cells, Cultured ; Cilia/*metabolism ; Cytoplasm/metabolism ; Female ; Hedgehog Proteins/deficiency/genetics/*metabolism ; Humans ; Kruppel-Like Transcription Factors/metabolism ; Male ; Membrane Proteins/chemistry/deficiency/metabolism ; Mice ; Nuclear Proteins/metabolism ; Organelles/*metabolism ; Receptors, Cell Surface/chemistry/metabolism ; Receptors, G-Protein-Coupled/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
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    Direct recording and molecular identification of the calcium channel of primary cilia (2013)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2013-12-18
    Beschreibung: A primary cilium is a solitary, slender, non-motile protuberance of structured microtubules (9+0) enclosed by plasma membrane. Housing components of the cell division apparatus between cell divisions, primary cilia also serve as specialized compartments for calcium signalling and hedgehog signalling pathways. Specialized sensory cilia such as retinal photoreceptors and olfactory cilia use diverse ion channels. An ion current has been measured from primary cilia of kidney cells, but the responsible genes have not been identified. The polycystin proteins (PC and PKD), identified in linkage studies of polycystic kidney disease, are candidate channels divided into two structural classes: 11-transmembrane proteins (PKD1, PKD1L1 and PKD1L2) remarkable for a large extracellular amino terminus of putative cell adhesion domains and a G-protein-coupled receptor proteolytic site, and the 6-transmembrane channel proteins (PKD2, PKD2L1 and PKD2L2; TRPPs). Evidence indicates that the PKD1 proteins associate with the PKD2 proteins via coiled-coil domains. Here we use a transgenic mouse in which only cilia express a fluorophore and use it to record directly from primary cilia, and demonstrate that PKD1L1 and PKD2L1 form ion channels at high densities in several cell types. In conjunction with an accompanying manuscript, we show that the PKD1L1-PKD2L1 heteromeric channel establishes the cilia as a unique calcium compartment within cells that modulates established hedgehog pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073646/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073646/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeCaen, Paul G -- Delling, Markus -- Vien, Thuy N -- Clapham, David E -- P01 NS072040/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- P30 HD18655/HD/NICHD NIH HHS/ -- T32 HL007572/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 12;504(7479):315-8. doi: 10.1038/nature12832.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston, 320 Longwood Avenue, Boston, Massachusetts 02115, USA [2]. ; Department of Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, USA. ; 1] Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston, 320 Longwood Avenue, Boston, Massachusetts 02115, USA [2] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336289" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Calcium Channels/deficiency/genetics/*metabolism ; Cell Division ; Cell Line ; Cell Membrane/metabolism ; Cells, Cultured ; Cilia/*metabolism ; HEK293 Cells ; Hedgehog Proteins/metabolism ; Humans ; Membrane Proteins/deficiency/genetics/metabolism ; Mice ; Mice, Transgenic ; Oncogene Proteins/metabolism ; Receptors, Cell Surface/deficiency/genetics/metabolism ; Receptors, G-Protein-Coupled/genetics/metabolism ; Trans-Activators/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
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    Primary cilia are not calcium-responsive mechanosensors (2016)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2016-03-24
    Beschreibung: Primary cilia are solitary, generally non-motile, hair-like protrusions that extend from the surface of cells between cell divisions. Their antenna-like structure leads naturally to the assumption that they sense the surrounding environment, the most common hypothesis being sensation of mechanical force through calcium-permeable ion channels within the cilium. This Ca(2+)-responsive mechanosensor hypothesis for primary cilia has been invoked to explain a large range of biological responses, from control of left-right axis determination in embryonic development to adult progression of polycystic kidney disease and some cancers. Here we report the complete lack of mechanically induced calcium increases in primary cilia, in tissues upon which this hypothesis has been based. We developed a transgenic mouse, Arl13b-mCherry-GECO1.2, expressing a ratiometric genetically encoded calcium indicator in all primary cilia. We then measured responses to flow in primary cilia of cultured kidney epithelial cells, kidney thick ascending tubules, crown cells of the embryonic node, kinocilia of inner ear hair cells, and several cell lines. Cilia-specific Ca(2+) influxes were not observed in physiological or even highly supraphysiological levels of fluid flow. We conclude that mechanosensation, if it originates in primary cilia, is not via calcium signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851444/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851444/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delling, M -- Indzhykulian, A A -- Liu, X -- Li, Y -- Xie, T -- Corey, D P -- Clapham, D E -- 5R01 DC000304/DC/NIDCD NIH HHS/ -- P30-HD 18655/HD/NICHD NIH HHS/ -- R01 DC000304/DC/NIDCD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 31;531(7596):656-60. doi: 10.1038/nature17426. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Image and Data Analysis Core (IDAC), Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007841" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Calcium/analysis/*metabolism ; Calcium Signaling ; Cilia/*metabolism ; Embryo, Mammalian/cytology ; Epithelial Cells/cytology ; Female ; Hair Cells, Auditory, Inner/cytology ; Kidney/cytology ; Male ; *Mechanotransduction, Cellular ; Mice ; Mice, Transgenic ; Models, Biological
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
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    Molecular dynamics of ion transport through the open conformation of a bacterial voltage-gated sodium channel (2013)
    National Academy of Sciences
    Details
    Publikationsdatum: 2013-03-29
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
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    Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-10-24
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
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    Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice (2007)
    National Academy of Sciences
    Details
    Publikationsdatum: 2007-11-07
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 9
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    Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system [Neuroscience] (2011)
    National Academy of Sciences
    Details
    Publikationsdatum: 2011-11-02
    Beschreibung: Detection and adaptation to cold temperature is crucial to survival. Cold sensing in the innocuous range of cold (〉10–15 °C) in the mammalian peripheral nervous system is thought to rely primarily on transient receptor potential (TRP) ion channels, most notably the menthol receptor, TRPM8. Here we report that TRP cation channel, subfamily C member 5 (TRPC5), but not TRPC1/TRPC5 heteromeric channels, are highly cold sensitive in the temperature range 37–25 °C. We found that TRPC5 is present in mouse and human sensory neurons of dorsal root ganglia, a substantial number of peripheral nerves including intraepithelial endings, and in the dorsal lamina of the spinal cord that receives sensory input from the skin, consistent with a potential TRPC5 function as an innocuous cold transducer in nociceptive and thermosensory nerve endings. Although deletion of TRPC5 in 129S1/SvImJ mice resulted in no temperature-sensitive behavioral changes, TRPM8 and/or other menthol-sensitive channels appear to underpin a much larger component of noxious cold sensing after TRPC5 deletion and a shift in mechanosensitive C-fiber subtypes. These findings demonstrate that highly cold-sensitive TRPC5 channels are a molecular component for detection and regional adaptation to cold temperatures in the peripheral nervous system that is distinct from noxious cold sensing.
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
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    Molecular dynamics simulation of a sodium channel [Computer Sciences] (2013)
    National Academy of Sciences
    Details
    Publikationsdatum: 2013-04-17
    Beschreibung: The crystal structure of the open conformation of a bacterial voltage-gated sodium channel pore from Magnetococcus sp. (NaVMs) has provided the basis for a molecular dynamics study defining the channel’s full ion translocation pathway and conductance process, selectivity, electrophysiological characteristics, and ion-binding sites. Microsecond molecular dynamics simulations permitted a complete...
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Erwartet Verfügbarkeit
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