Abstract
Neuropathic 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.
Footnotes
- Received May 22, 2018.
- Accepted August 20, 2018.
S.G.W. and S.D.D.-H. were supported by Center Grant [B9253-C] from the Rehabilitation Research Service, Department of Veterans Affairs, USA, and a gift from The Erythromelalgia Association. D.L.B. is a Wellcome Senior Clinical Scientist [Grant 202747/Z/16/Z]. A.C.T., I.B., and D.L.B. are members of the DOLORisk consortium funded by the European Commission Horizon 2020 [ID633491]. A.C.T. and D.L.B. are members of the International Diabetic Neuropathy Consortium, the Novo Nordisk Foundation [Grant NNF14SA0006]. The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. No potential conflicts of interest relevant to this article are reported.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics