1. Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies
- Author
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Yong Shi, Han Xiang Deng, Teepu Siddique, Marco Martina, Rafiq Huda, and Faisal Fecto
- Subjects
TRPV4 ,Cytoplasm ,Cell type ,DNA, Complementary ,Cell Survival ,Mutant ,Cell Cycle Proteins ,Gating ,Biology ,Models, Biological ,Biochemistry ,Calcium in biology ,Transient receptor potential channel ,Transient Receptor Potential Channels ,medicine ,Humans ,Patch clamp ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Genetics ,Microscopy, Confocal ,Models, Statistical ,Cell Membrane ,Neurodegeneration ,Nuclear Proteins ,Neurodegenerative Diseases ,Molecular Bases of Disease ,Cell Biology ,medicine.disease ,Axons ,Cell biology ,Electrophysiology ,Mutation ,Calcium Channels ,HeLa Cells - 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.
- Published
- 2011
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