Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7

Stadler T, o' Reilly A, Lampert A (2015)


Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 290

Pages Range: 6316-25

Journal Issue: 10

DOI: 10.1074/jbc.M114.605899

Abstract

The human voltage-gated sodium channel Nav1.7 plays a crucial role in transmission of noxious stimuli. The inherited pain disorder erythromelalgia (IEM) has been linked to Nav1.7 gain-of-function mutations. Here we show that the IEM-associated Q875E mutation located on the pore module of Nav1.7 produces a large hyperpolarizing shift (-18 mV) in the voltage dependence of activation. Three-dimensional homology modeling indicates that the side chains of Gln-875 and the gating charge Arg-214 of the domain I voltage sensor are spatially close in the activated conformation of the channel. We verified this proximity by using an engineered disulfide bridge approach. The Q875E mutation introduces a negative charge that may modify the local electrical field experienced by the voltage sensor and, upon activation, interact directly via a salt bridge with the Arg-214 gating charge residue. Together these processes could promote transition to, and stabilization of, the domain I voltage sensor in the activated conformation and thus produce the observed gain of function. In support of this hypothesis, an increase in the extracellular concentration of Ca(2+) or Mg(2+) reverted the voltage dependence of activation of the IEM mutant to near WT values, suggesting a cation-mediated electrostatic screening of the proposed interaction between Q875E and Arg-214.

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How to cite

APA:

Stadler, T., o' Reilly, A., & Lampert, A. (2015). Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7. Journal of Biological Chemistry, 290(10), 6316-25. https://doi.org/10.1074/jbc.M114.605899

MLA:

Stadler, Theresa, Andrias o' Reilly, and Angelika Lampert. "Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7." Journal of Biological Chemistry 290.10 (2015): 6316-25.

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