The novel activity of carbamazepine as an activation modulator extends from Na V 1.7 mutations to the Na V 1.8-S242T mutant channel from a patient with painful diabetic neuropathy

Neuropathic pain in patients carrying sodium channel gain-offunction mutations is generally refractory to pharmacotherapy. However, we have shown that pretreatment of cells with clinically achievable concentration of carbamazepine (CBZ; 30 mM) depolarizes the voltage dependence of activation in some Na V 1.7 mutations such as S241T, a novel CBZ mode of action of this drug. CBZ reduces the excitability of dorsal root ganglion (DRG) neurons expressing Na V 1.7-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 Na V 1.7, and whether this pharmacogenomic approach can be extended to other sodium channel subtypes, are not known. We report here the novel Na V 1.8-S242T mutation, which corresponds to the Na V 1.7-S241T mutation, in a patient with neuropathic pain and diabetic peripheral neuropathy. Voltage-clamp recordings demonstrated hyperpolarized and accelerated activation of Na V 1.8-S242T. Current-clamp recordings showed that Na V 1.8-S242T channels render DRG neurons hyperexcitable. Structural modeling shows that despite a substantial difference in the primary amino acid sequence of Na V 1.7 and Na V 1.8, the S242 (Na V 1.8) and S241 (Na V 1.7) 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 Na V 1.8-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, Na V 1.8.