Inhibition of Navβ4 Peptide-Mediated Resurgent Sodium Currents in Nav1.7 Channels by Carbamazepine, Riluzole, and Anandamide
- 25 July 2011
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 80 (4), 724-734
- https://doi.org/10.1124/mol.111.072751
Abstract
Paroxysmal extreme pain disorder (PEPD) and inherited erythromelalgia (IEM) are inherited pain syndromes arising from different sets of gain-of-function mutations in the sensory neuronal sodium channel isoform Nav1.7. Mutations associated with PEPD, but not IEM, result in destabilized inactivation of Nav1.7 and enhanced resurgent sodium currents. Resurgent currents arise after relief of ultra-fast open-channel block mediated by an endogenous blocking particle and are thought to influence neuronal excitability. As such, enhancement of resurgent currents may constitute a pathological mechanism contributing to sensory neuron hyperexcitability and pain hypersensitivity associated with PEPD. Furthermore, pain associated with PEPD, but not IEM, is alleviated by the sodium channel inhibitor carbamazepine. We speculated that selective attenuation of PEPD-enhanced resurgent currents might contribute to this therapeutic effect. Here we examined whether carbamazepine and two other sodium channel inhibitors, riluzole and anandamide, exhibit differential inhibition of resurgent currents. To gain further insight into the potential mechanism(s) of resurgent currents, we examined whether these inhibitors produced correlative changes in other properties of sodium channel inactivation. Using stably transfected human embryonic kidney 293 cells expressing wild-type Nav1.7 and the PEPD mutants T1464I and M1627K, we examined the effects of the three drugs on Navβ4 peptide-mediated resurgent currents. We observed a correlation between resurgent current inhibition and a drug-mediated increase in the rate of inactivation and inhibition of persistent sodium currents. Furthermore, although carbamazepine did not selectively target resurgent currents, anandamide strongly inhibited resurgent currents with minimal effects on the peak transient current amplitude, demonstrating that resurgent currents can be selectively targeted.This publication has 39 references indexed in Scilit:
- Temporal lobe epilepsy induces intrinsic alterations in Na channel gating in layer II medial entorhinal cortex neuronsNeurobiology of Disease, 2011
- Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navβ4 peptide‐mediated resurgent sodium currentsThe Journal of Physiology, 2011
- Control of transient, resurgent, and persistent current by open-channel block by Na channel β4 in cultured cerebellar granule neuronsProceedings of the National Academy of Sciences of the United States of America, 2010
- Riluzole protects against cardiac ischaemia and reperfusion damage via block of the persistent sodium currentBritish Journal of Pharmacology, 2010
- Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currentsJCI Insight, 2010
- Effects of Ranolazine on Wild-Type and Mutant hNav1.7 Channels and on DRG Neuron ExcitabilityMolecular Pain, 2010
- Subtype‐selective targeting of voltage‐gated sodium channelsBritish Journal of Pharmacology, 2009
- Paroxysmal extreme pain disorder mutations within the D3/S4–S5 linker of Nav1.7 cause moderate destabilization of fast inactivationThe Journal of Physiology, 2008
- Paroxysmal Extreme Pain Disorder M1627K Mutation in Human Nav1.7 Renders DRG Neurons HyperexcitableMolecular Pain, 2008
- A single sodium channel mutation produces hyper- or hypoexcitability in different types of neuronsProceedings of the National Academy of Sciences of the United States of America, 2006