Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension

作者：Brett A. McCray, Erika Diehl, Jeremy M. Sullivan, William H. Aisenberg, Nicholas W. Zaccor, Alexander R. Lau, Dominick J. Rich, Benedikt Goretzki, Ute A. Hellmich, Thomas E. Lloyd, Charlotte J. Sumner · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-21699-y · 被引用次数：58 · 研究领域：Ion Channels and Receptors、Ion channel regulation and function

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.