ArticleThe Journal of biological chemistry2015
Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- Article
- Hydropathicity-based prediction of pain-causing NaV1.7 variants.BMC bioinformatics · 2021Article
- Non-extensitivity and criticality of atomic hydropathicity around a voltage-gated sodium channel's pore: a modeling study.Journal of biological physics · 2021Article
- Uncoupling sodium channel dimers restores the phenotype of a pain-linked NaBritish journal of pharmacology · 2020Article
- Article
- Network topology of NaV1.7 mutations in sodium channel-related painful disorders.BMC systems biology · 2017Article
- Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain.Toxins · 2016Article
- Gain-of-Function Mutation W493R in the Epithelial Sodium Channel Allosterically Reconfigures Intersubunit Coupling.The Journal of biological chemistry · 2016Article
- Primary erythromelalgia: a review.Orphanet journal of rare diseases · 2015Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
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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