The Novel Activity of Carbamazepine as an Activation Modulator Extends from NaV1.7 Mutations to the NaV1.8-S242T Mutant Channel from a Patient with Painful Diabetic Neuropathy.

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.

• Authors: Chongyang Han, Andreas C Themistocleous, Mark Estacion, Fadia B Dib-Hajj, Iulia Blesneac, Lawrence Macala, Carl Fratter, David L Bennett, Stephen G Waxman, Sulayman D Dib-Hajj
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 94 Issue 5 Pg. 1256-1269 (11 2018) ISSN: 1521-0111 [Electronic] United States
• PMID: 30135145 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• NAV1.7 Voltage-Gated Sodium Channel
• NAV1.8 Voltage-Gated Sodium Channel
• SCN10A protein, human
• SCN9A protein, human
• Carbamazepine

Topics

• Aged
• Animals
• Carbamazepine (pharmacology)
• Diabetic Neuropathies (complications, genetics, physiopathology)
• Female
• Ganglia, Spinal (metabolism, physiopathology)
• Humans
• Male
• Membrane Potentials
• Mice
• Mutation
• NAV1.7 Voltage-Gated Sodium Channel (genetics)
• NAV1.8 Voltage-Gated Sodium Channel (genetics)
• Pain (complications, physiopathology)
• Pain Measurement
• Patch-Clamp Techniques