【摘 要】
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Mucolipin TRP channel 1 (TRPML1) is an inwardly rectifying Ca2+-permeable channel in late endosomes and lysosomes.Loss-of-function mutations in the human TR
【机 构】
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Molecular,Cellular and Developmental Biology Department,University of Michigan Ann Arbor,Michigan,US
【出 处】
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The 3rd Ion Channel Conference: Ion channels-Structure, Func
论文部分内容阅读
Mucolipin TRP channel 1 (TRPML1) is an inwardly rectifying Ca2+-permeable channel in late endosomes and lysosomes.Loss-of-function mutations in the human TRPML1 gene cause a devastating pediatric neurodegenerative disease called type V Mucolipidosis (ML4).We recently identified PI(3,5)P2, a phosphoinositide localized predominantly in the late endosome and lysosome, as an endogenous activator of TRPML1 ((Dong et al., 2010.1:38 | DOI: 10.1038/ncomms1037)).We now report a membrane-permeable small-molecule synthetic agonist for TRPML1, Mucolipin-Synthetic Agonist 1 (ML-SA1).By direct patch-clamping of endolysosomal membranes, we found that ML-SA1 potently activates recombinant TRPML1, as well as endogenous TRPML-like currents in several cell types.The activation effect of ML-SA1 can be further potentiated by PI(3,5)P2,suggestive of a synergism between the two agonists.By using lysosome-targeting GCaMP3-based Ca2+ sensors, we found that ML-SA1 evokes TRPML 1-dependent Ca2+ release from endolysosomes in intact cells.In summary, the TRPMLl-specific chemical agonist will provide a valuable tool for studying the intracellular functions of TRPML1, providing a potential therapeutic approach for treating ML4 disease.
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