• Chongyang Han, Andreas C Themistocleous, Mark Estacion, Fadia B Dib-Hajj, Iulia Blesneac, Lawrence Macala, Carl Fratter, David L Bennett, Stephen G Waxman, and Sulayman D Dib-Hajj.
• Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut (C.H., M.E., F.B.D.-H., L.M., S.G.W., S.D.D.-H.); Center for restoration of Nervous System Function, Veterans Affairs Medical Center, West Haven, Connecticut (C.H., M.E., F.B.D.-H., L.M., S.G.W., S.D.D.-H.); Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom (A.C.T., I.B., D.L.B.); Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (A.C.T.); and Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom (C.F.).
• Mol. Pharmacol. 2018 Nov 1; 94 (5): 1256-1269.

AbstractNeuropathic pain in patients carrying sodium channel gain-of-function mutations is generally refractory to pharmacotherapy. However, we have shown that pretreatment of cells with clinically achievable concentration of carbamazepine (CBZ; 30 μM) depolarizes the voltage dependence of activation in some NaV1.7 mutations such as S241T, a novel CBZ mode of action of this drug. CBZ reduces the excitability of dorsal root ganglion (DRG) neurons expressing NaV1.7-S241T mutant channels, and individuals carrying the S241T mutation respond to treatment with CBZ. Whether the novel activation-modulating activity of CBZ is specific to NaV1.7, and whether this pharmacogenomic approach can be extended to other sodium channel subtypes, are not known. We report here the novel NaV1.8-S242T mutation, which corresponds to the NaV1.7-S241T mutation, in a patient with neuropathic pain and diabetic peripheral neuropathy. Voltage-clamp recordings demonstrated hyperpolarized and accelerated activation of NaV1.8-S242T. Current-clamp recordings showed that NaV1.8-S242T channels render DRG neurons hyperexcitable. Structural modeling shows that despite a substantial difference in the primary amino acid sequence of NaV1.7 and NaV1.8, the S242 (NaV1.8) and S241 (NaV1.7) residues have similar position and orientation in the domain I S4-S5 linker of the channel. Pretreatment with a clinically achievable concentration of CBZ corrected the voltage dependence of activation of NaV1.8-S242T channels and reduced DRG neuron excitability as predicted from our pharmacogenomic model. These findings extend the novel activation modulation mode of action of CBZ to a second sodium channel subtype, NaV1.8.Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

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