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Cited by 57Ion Channels and ReceptorsHereditary Neurological DisordersCalcium signaling and nucleotide metabolism

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

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McCray, Brett A., Diehl, Erika, Sullivan, Jeremy M., Aisenberg, William H., Zaccor, Nicholas W., Lau, Alexander R., Rich, Dominick J., Goretzki, Benedikt +3 more·2021·Nature Communications
DOI 10.1038/s41467-021-21699-yPMC PMC7933254
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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.

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  • Misregulation of RhoA might contribute to side effects of taxanes, such as neuropathy.

    “On the other hand, misregulation of RhoA might contribute to the side effects of taxanes, such as neuropathy 82,83 .”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [82]

    The Results section on TRPV4–RhoA interactions links excessive RhoA activity to neuropathy caused by TRPV4 mutations. It does not address taxanes or establish that RhoA misregulation contributes to their side effects (searched: taxanes, paclitaxel, docetaxel). (LLM, conf=0.87)

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Authors
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.
Affiliations
  • Johns Hopkins University (US)
  • Goethe University Frankfurt (DE)
Corresponding author
  • McCray, Brett A.
  • Sumner, Charlotte J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-03-04
Volume
12
Issue
1
Pages
1444-1444
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-21699-y
PMC
PMC7933254
OpenAlex
W3135740603
Cited by
57
References
3
Citations by year
2026: 10 · 2025: 10 · 2024: 14 · 2023: 10 · 2022: 9 · 2021: 4
FWCI
5.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS102509, NS094239, NS082563)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
TRPV4, RhoA, peripheral neuropathy, skeletal dysplasia, missense mutations, N-terminal domain, protein-protein interaction, neurite outgrowth, cytoskeletal remodeling, dominant negative mutation, Drosophila model, calcium channels
MeSH terms
Animals, Calcium, Cell Line, Chlorocebus aethiops, Drosophila, Humans, Actin Cytoskeleton, Peripheral Nervous System Diseases, Neurites, COS Cells, rhoA GTP-Binding Protein, TRPV Cation Channels, HEK293 Cells

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