title: Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating.
abstract: The Nav1.7 sodium channel is preferentially expressed in most nociceptive dorsal root ganglion neurons and in sympathetic neurons. Inherited erythromelalgia (IEM, also known as erythermalgia), an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth, has been linked to mutations in Nav1.7. Recently, a substitution of Ser-241 by threonine (S241T) in the domain I S4-S5 linker of Nav1.7 was identified in a family with IEM. To investigate the possible causative role of this mutation in the pathophysiology of IEM, we used whole-cell voltage-clamp analysis to study the effects of S241T on Nav1.7 gating in HEK293 cells. We found a hyperpolarizing shift of activation midpoint by 8.4 mV, an accelerated time to peak, slowing of deactivation, and an increase in the current in response to small, slow depolarizations. Additionally, S241T produced an enhancement of slow inactivation, shifting the midpoint by -12.3 mV. Because serine and threonine have similar biochemical properties, the S241T substitution suggested that the size of the side chain at this position affected channel gating. To test this hypothesis, we investigated the effect of S241A and S241L substitutions on the gating properties of Nav1.7. Although S241A did not alter the properties of the channel, S241L mimicked the effects of S241T. We conclude that the linker between S4 and S5 in domain I of Nav1.7 modulates gating of this channel, and that a larger side chain at position 241 interferes with its gating mechanisms.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Lynda
authors.initials: L
authors.lastname: Tyrrell
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000200:Action Potentials; D002460:Cell Line; D004916:Erythromelalgia / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials; D008956:Models, Chemical; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D012694:Serine / Q000737:chemistry; D015222:Sodium Channels / Q000235:genetics*; D013912:Threonine / Q000737:chemistry; D014162:Transfection
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D013912:Threonine; D012694:Serine