Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies

Faisal Fecto, Yong Shi, Rafiq Huda, Marco Martina, Teepu Siddique, Han-Xiang Deng*

*Corresponding author for this work

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Mutations in TRPV4 have been linked to three distinct axonal neuropathies. However, the pathogenic mechanism underlying these disorders remains unclear. Both gain and loss of calcium channel activity of the mutant TRPV4 have been suggested. Here, we show that the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types. Patch clamp experiments showed that cells expressing mutant TRPV4 have much larger whole-cell currents than those expressing the wild-type TRPV4 channel. Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance. These data support the hypothesis that a "gain of function" mechanism, possibly leading to increased intracellular calcium influx, underlies the pathogenesis of the TRPV4-linked axonal neuropathies, and may have immediate implications for designing rational therapies.

Original languageEnglish (US)
Pages (from-to)17281-17291
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number19
DOIs
StatePublished - May 13 2011

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Calcium Channels
Toxicity
Clamping devices
Cytotoxicity
Cells
Calcium
Mutation
Experiments
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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abstract = "Mutations in TRPV4 have been linked to three distinct axonal neuropathies. However, the pathogenic mechanism underlying these disorders remains unclear. Both gain and loss of calcium channel activity of the mutant TRPV4 have been suggested. Here, we show that the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types. Patch clamp experiments showed that cells expressing mutant TRPV4 have much larger whole-cell currents than those expressing the wild-type TRPV4 channel. Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance. These data support the hypothesis that a {"}gain of function{"} mechanism, possibly leading to increased intracellular calcium influx, underlies the pathogenesis of the TRPV4-linked axonal neuropathies, and may have immediate implications for designing rational therapies.",
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Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. / Fecto, Faisal; Shi, Yong; Huda, Rafiq; Martina, Marco; Siddique, Teepu; Deng, Han-Xiang.

In: Journal of Biological Chemistry, Vol. 286, No. 19, 13.05.2011, p. 17281-17291.

Research output: Contribution to journalArticle

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AU - Fecto, Faisal

AU - Shi, Yong

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AU - Deng, Han-Xiang

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