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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 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.

SUBMITTER: Huang CW

PROVIDER: S-EPMC6706385 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Huang Chiung-Wei CW Lai Hsing-Jung HJ Huang Po-Yuan PY Lee Ming-Jen MJ Kuo Chung-Chin CC

Scientific reports 20190822 1

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 ...[more]

PMID: 31439884

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Project description:Primary erythromelalgia (PE) is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the ?-subunit of the voltage-gated sodium channel, Na(v)1.7, were found to be responsible for PE. Three missense mutations of SCN9A gene have recently been identified in Taiwanese patients including a familial (I136V) and two sporadic mutations (I848T, V1316A). V1316A is a novel mutation and has not been characterized yet. Topologically, I136V is located in DI/S1 segment and both I848T and V1316A are located in S4-S5 linker region of DII and DIII domains, respectively. To characterize the elelctrophysiological manifestations, the channel conductance with whole-cell patch clamp was recorded on the over-expressed Chinese hamster overy cells. As compared with wild type, the mutant channels showed a significant hyperpolarizing shift in voltage dependent activation and a depolarizing shift in steady-state fast inactivation. The recovery time from channel inactivation is faster in the mutant than in the wild type channels. Since warmth can trigger and exacerbate symptoms, we then examine the influence of tempearture on the sodium channel conduction. At 35°C, I136V and V1316A mutant channels exhibit a further hyperpolarizing shift at activation as compared with wild type channel, even though wild type channel also produced a significant hyperpolarizing shift compared to that of 25°C. High temperature caused a significant depolarizing shift in steady-state fast inactivation in all three mutant channels. These findings may confer to the hyperexcitability of sensory neurons, especially at high temperature. In order to identifying an effective treatment, we tested the IC?? values of selective sodium channel blockers, lidocaine and mexiletine. The IC?? for mexiletine is lower for I848T mutant channel as compared to that of the wild type and other two mutants which is comparable to the clinical observations.

Dataset Information

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

Publications

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

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