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| Item Type: | Article |
|---|---|
| Title: | Cold-aggravated pain in humans caused by a hyperactive Na(V)1.9 channel mutant |
| Creators Name: | Leipold, E., Hanson-Kahn, A., Frick, M., Gong, P., Bernstein, J.A., Voigt, M., Katona, I., Oliver Goral, R., Altmüller, J., Nürnberg, P., Weis, J., Hübner, C.A., Heinemann, S.H. and Kurth, I. |
| Abstract: | Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel Na(V)1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the Na(V)1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to Na(V)1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of Na(V)1.9 hyperactivity. |
| Keywords: | Cold Temperature, Inbred C57BL Mice, Missense Mutation, NAV1.9 Voltage-Gated Sodium Channel, Pain, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 6 |
| Page Range: | 10049 |
| Date: | 8 December 2015 |
| Official Publication: | https://doi.org/10.1038/ncomms10049 |
| PubMed: | View item in PubMed |
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