TY - JOUR T1 - The Novel Activity of Carbamazepine as an Activation Modulator Extends from Na<sub>V</sub>1.7 Mutations to the Na<sub>V</sub>1.8-S242T Mutant Channel from a Patient with Painful Diabetic Neuropathy JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1256 LP - 1269 DO - 10.1124/mol.118.113076 VL - 94 IS - 5 AU - Chongyang Han AU - Andreas C. Themistocleous AU - Mark Estacion AU - Fadia B. Dib-Hajj AU - Iulia Blesneac AU - Lawrence Macala AU - Carl Fratter AU - David L. Bennett AU - Stephen G. Waxman AU - Sulayman D. Dib-Hajj Y1 - 2018/11/01 UR - http://molpharm.aspetjournals.org/content/94/5/1256.abstract N2 - 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. ER -