title: Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies.
abstract: Mutations in TRPV4 have been linked to three distinct axonal neuropathies. However, the pathogenic mechanism underlying these disorders remains unclear. Both gain and loss of calcium channel activity of the mutant TRPV4 have been suggested. Here, we show that the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types. Patch clamp experiments showed that cells expressing mutant TRPV4 have much larger whole-cell currents than those expressing the wild-type TRPV4 channel. Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance. These data support the hypothesis that a "gain of function" mechanism, possibly leading to increased intracellular calcium influx, underlies the pathogenesis of the TRPV4-linked axonal neuropathies, and may have immediate implications for designing rational therapies.
authors: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Faisal
authors: F
authors: Fecto
authors: Yong
authors: Y
authors: Shi
authors: Rafiq
authors: R
authors: Huda
authors: Marco
authors: M
authors: Martina
authors: Teepu
authors: T
authors: Siddique
authors: Han-Xiang
authors: HX
authors: Deng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D015233:Models, Statistical; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015220:Calcium Channels; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; C470309:MAD2L1BP protein, human; D009687:Nuclear Proteins; D050051:Transient Receptor Potential Channels