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

Abstract

Inherited erythromelalgia (IEM), caused by mutations in Na v 1.7 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 Na v 1.7 channels with three different mutations, p.I136V, p. I848T, and p.V1316A, both in vitro and in vivo . In vitro b iophysical 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 Na v 1.7 channels responsible for the genesis of resurgent currents.

Changes of Resurgent Na+ Currents in the Nav1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia

“…Resurgent Na + currents can be observed in voltage-gated Na + channels containing a Na v β4 peptide at the repolarization stage [21]. Figure 4 shows the resurgent Na + currents elicited at the repolarization (0 to −100 mV) following a prepulse depolarization at +40 mV in the p.V445M mutant and WT Na v 1.4 channels.…”

“…The homology modeling procedure was performed using methods similar to those used in our previous study [13,21]. A homology model of the WT Na v 1.4 channel encoded by the SCN4A gene was built from X-ray crystal structure data of the human voltage-gated Na v 1.4 channel (human Na v 1.4; PDB code: 6AGF).…”

“…Sequences of the three inter-domain linkers of the WT Na v 1.4 channel (DI-DII linker, A447-P578; DII-DIII linker, L798-W1032; and DIII-DIV linker, G1292-A1354) were inserted into positions between the domains (DI-DIV) via homology modeling based on the WT human Na v 1.4 channel. The aligned sequences were then processed using Discovery Studio 2018 (Dassault Systèmes, Vélizy-Villacoublay, France) to assign the relative positions and generate the secondary structure of the WT human Na v 1.4 channel [13,21].…”

Primary Erythromelalgia Complicated by Cellulitis: A Case Report and Review of Literature

“…It has been postulated that at higher temperatures, mutant VGSC in sensory neurons, sympathetic neurons and skin vasculature simultaneously discharge impulses at high frequency leading to pain hypersensitivity with release of inflammatory mediators, dysautonomia and vasodilation. Thus, shunting blood away from the capillary beds, inducing hypoxia and inflammation at the site [2,22,28,29].…”

“…Most cases of primary EM are triggered by increased skin temperature, internally by increased metabolism (running, jogging) or externally by environmental temperature (summers, humid work atmosphere) [2,3]. The inability to thermoregulate coupled with increased pain sensitivity leads to characteristic burning pain [22,28]. The triggers identified by patients are confirmed during disease workup.…”