Anomalous enhancement of resurgent Na+ currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia

Chiung-Wei Huang,Ming-Jen Lee,Chung-Chin Kuo,Po-Yuan Huang,Hsing-Jung Lai

doi:10.1038/s41598-019-48672-6

Abstract

Inherited 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–dependent 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–dependent changes in steady–state 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 (50–100 ms), the increase of inward rectification in current–voltage curve, and the increase of refractoriness at the interpulse interval of 2–6 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–enhanced pain in IEM could be attributed to deranged temperature dependence of Nav1.7 channels responsible for the genesis of resurgent currents.

Highlights

Primary erythromelalgia or inherited erythromelalgia (IEM; OMIN 133020) is an autosomal dominant chronic neurological disorder caused by mutations in human SCN9A gene encoding α subunit of Nav1.7 channel, which is abundantly expressed in trigeminal, sympathetic, and dorsal root ganglion neurons[1,2,3,4]
We investigated the effect of temperature changes on the molecular behavior of the wild–type (WT) and different mutant Nav1.7 channels both in vitro and in vivo, endeavoring to identify the key pathophysiological elements responsible for the symptomatic pathogenesis of Inherited erythromelalgia (IEM)
The IEM patients show increased refractoriness and reduced superexcitability in recovery cycle (RC), and reduced threshold elevation at late hyperpolarizing threshold electrotonus (TE), both implying abnormalities in the recovery from inactivation in Na+ channels. These nerve excitability tests (NET) abnormalities are effectively ameliorated by local cooling. These findings indicate that deranged resurgent Na+ currents, which are consequences of deranged temperature dependence of the kinetics of relevant molecular transitions, play the major and crucial role in the pathogenesis of IEM

Summary

Introduction

Primary erythromelalgia or inherited erythromelalgia (IEM; OMIN 133020) is an autosomal dominant chronic neurological disorder caused by mutations in human SCN9A gene encoding α subunit of Nav1.7 channel, which is abundantly expressed in trigeminal, sympathetic, and dorsal root ganglion neurons[1,2,3,4]. We investigated the effect of temperature changes on the molecular behavior of the wild–type (WT) and different mutant Nav1.7 channels both in vitro and in vivo (with nerve excitability test, NET), endeavoring to identify the key pathophysiological elements responsible for the symptomatic pathogenesis of IEM. The IEM patients show increased refractoriness and reduced superexcitability in recovery cycle (RC), and reduced threshold elevation at late hyperpolarizing threshold electrotonus (TE), both implying abnormalities in the recovery from inactivation in Na+ channels These NET abnormalities are effectively ameliorated by local cooling. These findings indicate that deranged resurgent Na+ currents, which are consequences of deranged temperature dependence of the kinetics of relevant molecular transitions, play the major and crucial role in the pathogenesis of IEM

Methods

Results

Conclusion