@article{3324622f3e7b4093857abe3cb4547db8,
title = "Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension",
abstract = "TRPV4 is a cell surface-expressed calcium-permeable cation channel that mediates cell-specific effects on cellular morphology and function. Dominant missense mutations of TRPV4 cause distinct, tissue-specific diseases, but the pathogenic mechanisms are unknown. Mutations causing peripheral neuropathy localize to the intracellular N-terminal domain whereas skeletal dysplasia mutations are in multiple domains. Using an unbiased screen, we identified the cytoskeletal remodeling GTPase RhoA as a TRPV4 interactor. TRPV4-RhoA binding occurs via the TRPV4 N-terminal domain, resulting in suppression of TRPV4 channel activity, inhibition of RhoA activation, and extension of neurites in vitro. Neuropathy but not skeletal dysplasia mutations disrupt TRPV4-RhoA binding and cytoskeletal outgrowth. However, inhibition of RhoA restores neurite length in vitro and in a fly model of TRPV4 neuropathy. Together these results identify RhoA as a critical mediator of TRPV4-induced cell structure changes and suggest that disruption of TRPV4-RhoA binding may contribute to tissue-specific toxicity of TRPV4 neuropathy mutations.",
author = "McCray, {Brett A.} and Erika Diehl and Sullivan, {Jeremy M.} and Aisenberg, {William H.} and Zaccor, {Nicholas W.} and Lau, {Alexander R.} and Rich, {Dominick J.} and Benedikt Goretzki and Hellmich, {Ute A.} and Lloyd, {Thomas E.} and Sumner, {Charlotte J.}",
note = "Funding Information: This work was supported by K08 NS102509 (B.A.M.), Inherited Neuropathies Consortium Fellowship (B.A.M.), American Academy of Neurology Neuroscience Research Training Fellowship (B.A.M.), TransMED Ph.D. Fellowship (E.D.), Fulbright Ph.D. Fellowship (E.D.), Sibylle Kalkhof-Rose Stiftung Fellowship (E.D.), NIH (NINDS) F31 NS105404 (W.H.A.), Max Planck Graduate Centre (MPGC) Ph.D. Fellowship (B.G.), Centre for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, funded by the state of Hesse (U.A.H.), the Naturwissenschaftliches-Medizinisches For-schungszentrum (NMFZ) Mainz (U.A.H.), NIH (NINDS) R01 NS094239 and NS082563 (T.E.L.), NIH (NINDS) R01 NS115475 (C.J.S.), and Muscular Dystrophy Association 629305 (C.J.S). Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40ODO18537) were used in this study. We thank the Johns Hopkins Institute for Basic Biomedical Sciences Microscope Facility and Hoku West-Foyle for assistance with FRET image acquisition and analysis. This facility was supported by the Office of the Director and the NIGMS of the NIH under award number S10OD023548. We thank the Johns Hopkins Mass Spectrometry and Proteomics Facility for assistance with liquid chromatography-mass spectrometry data acquisition and analysis. We thank Natalia Nedelsky for paper editing and graphical assistance. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-21699-y",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}