Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10049
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [KU 1587/3-1, LE 2338/3-1]
- 'DFG Heisenberg Professorship' [KU 1587/4-1]
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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 Na(V)1.9, 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.
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