Leipold, Enrico, Hanson-Kahn, Andrea, Frick, Miya, Gong, Ping, Bernstein, Jonathan A., Voigt, Martin, Katona, Istvan ORCID: 0000-0002-0955-8911, Goral, R. Oliver, Altmueller, Janine, Nuernberg, Peter, Weis, Joachim ORCID: 0000-0003-3280-6773, Huebner, Christian A., Heinemann, Stefan H. ORCID: 0000-0002-4144-0251 and Kurth, Ingo ORCID: 0000-0002-5642-8378 (2015). Cold-aggravated pain in humans caused by a hyperactive Na(V)1.9 channel mutant. Nat. Commun., 6. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Leipold, EnricoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanson-Kahn, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frick, MiyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gong, PingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernstein, Jonathan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voigt, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katona, IstvanUNSPECIFIEDorcid.org/0000-0002-0955-8911UNSPECIFIED
Goral, R. OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weis, JoachimUNSPECIFIEDorcid.org/0000-0003-3280-6773UNSPECIFIED
Huebner, Christian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinemann, Stefan H.UNSPECIFIEDorcid.org/0000-0002-4144-0251UNSPECIFIED
Kurth, IngoUNSPECIFIEDorcid.org/0000-0002-5642-8378UNSPECIFIED
URN: urn:nbn:de:hbz:38-384923
DOI: 10.1038/ncomms10049
Journal or Publication Title: Nat. Commun.
Volume: 6
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
OF-FUNCTION MUTATIONS; SODIUM-CHANNEL; SENSORY NEURONS; NA+ CURRENT; K+ CHANNEL; S4-S5 LINKER; NEUROPATHY; EXCITABILITY; MOUSE; SCN9AMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/38492

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