Anomalous enhancement of resurgent Na+ currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia
Journal
Scientific Reports
Journal Volume
9
Journal Issue
1
Pages
12251
ISSN
2045-2322
Date Issued
2019-12-01
Author(s)
Abstract
AbstractInherited erythromelalgia (IEM), caused by mutations in Nav1.7 channel is characterized by episodic neuropathic pain triggered especially by warm temperature. However, the mechanism underlying the temperature�Vdependent episodic attacks of IEM remains elusive. We investigated the electrophysiological effect of temperature changes on Nav1.7 channels with three different mutations, p.I136V, p. I848T, and p.V1316A, both in vitro and in vivo. In vitro biophysical studies of the mutant channels show consistent temperature-dependent enhancement of the relative resurgent currents if normalized to the transient currents, as well as temperature-dependent changes in the time to peak and the kinetics of decay of the resurgent currents, but no congruent temperature�Vdependent changes in steady�Vstate parameters such as shift of activation/inactivation curves and changes of the absolute size of the window or resurgent currents. In vivo nerve excitability tests (NET) in IEM patients reveal the essentially normal indices of NET at a single stimulus. However, there are evident abnormalities if assessed with preconditioning pulses, such as the decrease of threshold elevation in hyperpolarizing threshold electrotonus (50�V100?ms), the increase of inward rectification in current�Vvoltage curve, and the increase of refractoriness at the interpulse interval of 2�V6?ms in recovery cycle, probably also implicating derangements in temperature dependence of inactivation and of recovery from inactivation in the mutant channels. The pathogenesis of heat�Venhanced pain in IEM could be attributed to deranged temperature dependence of Nav1.7 channels responsible for the genesis of resurgent currents.
SDGs
Publisher
Nature Publishing Group
Type
journal article