McCray, B.A., Diehl, E., Sullivan, J.M., Aisenberg, W.H., Zaccor, N.W., Lau, A.R., Rich, D.J., Goretzki, B., Hellmich, U.A., Lloyd, T.E., Sumner, C.J. (2021). Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension.  Nat. Commun. 12(1): 1444.

FBrf0248485

Research paper

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.

PMC7933254 (PMC) (EuropePMC)