ArticleThe Journal of general physiology2007
A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore.
Article in The Journal of general physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers, 2 of them syntheses that pooled it.
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Who cites it
115 citing papers in PubMed, 2 syntheses or guidelines pooled it, 167 citations in OpenAlex.
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- Diagnostics and therapy of muscle channelopathies--Guidelines of the Ulm Muscle Centre.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2008Guideline
- Article
- Review
- Molecular genetics of skeletal muscle channelopathies.Journal of human genetics · 2025Review
- The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.The Journal of general physiology · 2025Article
- Voltage sensors.Molecular pharmacology · 2025Review
- ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS.bioRxiv : the preprint server for biology · 2024Article
- Pathogenic gating pore current conducted by autism-related mutations in the NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Periodic paralysis.Handbook of clinical neurology · 2024Review
- Periodic paralysis across the life course: age-related phenotype transition and sarcopenia overlap.Frontiers in neurology · 2024Review
- Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.The Journal of general physiology · 2024Article
- Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology.Channels (Austin, Tex.) · 2023Review
- Ion currents through the voltage sensor domain of distinct families of proteins.Journal of biological physics · 2023Review
- Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation.Biomaterials · 2023Article
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells.Disease models & mechanisms · 2023Article
- Case report: A novelFrontiers in neurology · 2023Article
- CaHandbook of experimental pharmacology · 2023Article
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
55 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The heritable muscle disorder hypokalemic periodic paralysis (HypoPP) is characterized by attacks of flaccid weakness, brought on by sustained sarcolemmal depolarization. HypoPP is genetically linked to missense mutations at charged residues in the S4 voltage-sensing segments of either CaV1.1 (the skeletal muscle L-type Ca(2+) channel) or NaV1.4 (the skeletal muscle voltage-gated Na(+) channel). Although these mutations alter the gating of both channels, these functional defects have proven insufficient to explain the sarcolemmal depolarization in affected muscle. Recent insight into the topology of the S4 voltage-sensing domain has aroused interest in an alternative pathomechanism, wherein HypoPP mutations might generate an aberrant ionic leak conductance by unblocking the putative aqueous crevice ("gating-pore") in which the S4 segment resides. We tested the rat isoform of NaV1.4 harboring the HypoPP mutation R663H (human R669H ortholog) at the outermost arginine of S4 in domain II for a gating-pore conductance. We found that the mutation R663H permits transmembrane permeation of protons, but not larger cations, similar to the conductance displayed by histidine substitution at Shaker K(+) channel S4 sites. These results are consistent with the notion that the outermost charged residue in the DIIS4 segment is simultaneously accessible to the cytoplasmic and extracellular spaces when the voltage sensor is positioned inwardly. The predicted magnitude of this proton leak in mature skeletal muscle is small relative to the resting K(+) and Cl(-) conductances, and is thus not likely to fully account for the aberrant sarcolemmal depolarization underlying the paralytic attacks. Rather, it is possible that a sustained proton leak may contribute to instability of V(REST) indirectly, for instance, by interfering with intracellular pH homeostasis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.