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A sodium channel gene SCN9A polymorphism that increases nociceptor excitability
Author(s) -
Estacion Mark,
Harty T. Patrick,
Choi JinSung,
Tyrrell Lynda,
DibHajj Sulayman D.,
Waxman Stephen G.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21895
Subject(s) - nociceptor , sodium channel , polymorphism (computer science) , nav1 , gene , neuroscience , medicine , sodium , chemistry , genetics , psychology , biology , nociception , receptor , genotype , organic chemistry
Sodium channel Na V 1.7, encoded by the SCN9A gene, is preferentially expressed in nociceptive primary sensory neurons, where it amplifies small depolarizations. In studies on a family with inherited erythromelalgia associated with Na V 1.7 gain‐of‐function mutation A863P, we identified a nonsynonymous single‐nucleotide polymorphism within SCN9A in the affected proband and several unaffected family members; this polymorphism (c. 3448C&T, Single Nucleotide Polymorphisms database rs6746030, which produces the amino acid substitution R1150W in human Na V 1.7 [hNa V 1.7]) is present in 1.1 to 12.7% of control chromosomes, depending on ethnicity. In this study, we examined the effect of the R1150W substitution on function of the hNa V 1.7 channel, and on the firing of dorsal root ganglion (DRG) neurons in which this channel is normally expressed. We show that this polymorphism depolarizes activation (7.9–11mV in different assays). Current‐clamp analysis shows that the 1150W allele depolarizes (6mV) resting membrane potential and increases (∼2‐fold) the firing frequency in response to depolarization in DRG neurons in which it is present. Our results suggest that polymorphisms in the Na V 1.7 channel may influence susceptibility to pain. Ann Neurol 2009;66:862–866