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

Nat Commun. 2021 Mar 4;12(1):1444. doi: 10.1038/s41467-021-21699-y.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Animals
  • COS Cells
  • Calcium / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • Drosophila
  • HEK293 Cells
  • Humans
  • Neurites / metabolism*
  • Peripheral Nervous System Diseases / genetics*
  • TRPV Cation Channels / genetics*
  • TRPV Cation Channels / metabolism*
  • rhoA GTP-Binding Protein / metabolism*


  • TRPV Cation Channels
  • TRPV4 protein, human
  • RHOA protein, human
  • rhoA GTP-Binding Protein
  • Calcium