PubMed 26645915

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1 , Nav1.9

Title: Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant.

Authors: Enrico Leipold, Andrea Hanson-Kahn, Miya Frick, Ping Gong, Jonathan A Bernstein, Martin Voigt, István Katona, R Oliver Goral, Janine Altmüller, Peter Nürnberg, Joachim Weis, Christian A Hübner, Stefan H Heinemann, Ingo Kurth

Journal, date & volume: Nat Commun, 2015 , 6, 10049

PubMed link:

Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 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 NaV1.9. 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 NaV1.9 hyperactivity.