ArticleThe Journal of physiology2006
Isoform-dependent interaction of voltage-gated sodium channels with protons.
Article in The Journal of physiology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 41 citations in OpenAlex.
- Voltage-gated sodium channels in cancers.Biomarker research · 2024Review
- Ion channel selectivity through ion-modulated changes of selectivity filter pProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Sodium channels and the ionic microenvironment of breast tumours.The Journal of physiology · 2023Article
- Determinants of conductance of a bacterial voltage-gated sodium channel.Biophysical journal · 2021Article
- pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology.Cancers · 2020Review
- Independent evolution of pain insensitivity in African mole-rats: origins and mechanisms.Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology · 2020Review
- Cationic Modulation of Voltage-Gated Sodium Channel (Nav1.5): Neonatal Versus Adult Splice Variants-1. Monovalent (HBioelectricity · 2019Article
- Cationic Modulation of Voltage-Gated Sodium Channel (Nav1.5): Neonatal Versus Adult Splice Variants-2. Divalent (CdBioelectricity · 2019Article
- Opening TRPP2 (Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels.Scientific reports · 2018Article
- Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3.Channels (Austin, Tex.) · 2018Article
- Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2014Review
- Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Extracellular protons inhibit charge immobilization in the cardiac voltage-gated sodium channel.Biophysical journal · 2013Article
- Proton sensors in the pore domain of the cardiac voltage-gated sodium channel.The Journal of biological chemistry · 2013Article
- Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine.Frontiers in pharmacology · 2013Article
- Acidosis differentially modulates inactivation in na(v)1.2, na(v)1.4, and na(v)1.5 channels.Frontiers in pharmacology · 2012Article
- Extracellular proton modulation of the cardiac voltage-gated sodium channel, Nav1.5.Biophysical journal · 2011Article
- Voltage-gated Na channel selectivity: the role of the conserved domain III lysine residue.The Journal of general physiology · 2008Review
- Calcium block of single sodium channels: role of a pore-lining aromatic residue.Biophysical journal · 2007Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Protons are potent physiological modifiers of voltage-gated Na(+) channels, shifting the voltage range of channel gating and reducing current magnitude (pK(a) approximately 6). We recently showed that proton block of the skeletal muscle isoform (Na(V)1.4) resulted from protonation of the four superficial carboxylates in the outer vestibule of the channel. We concluded that the large local negative electrostatic field shifted the outer vestibule carboxylate pK(a) into the physiological range. However, block was not complete; the best-fit titration curves yielded an acid pH asymptote of 10-15%, suggesting that the selectivity filter carboxylates may not be protonated. Using HEK 293 cells stably expressing different isoforms, each with varying channel density, we demonstrate that a pH-independent current is found in Na(V)1.4, but not in the cardiac isoform (Na(V)1.5). Mutational studies showed that absence of the pH-independent current in Na(V)1.5 could be ascribed to the cysteine in domain I, just above the selectivity filter aspartate (Cys373). We suggest that this cysteine can be protonated in acid solution to produce a positive charge that blocks the pore. Competition between protons and Na(+) did not exist for Na(+) concentrations between 1 and 140 mm. The residual current in acid solution, when the cysteine is absent, confirms that over the range of pH values that can be achieved physiologically, the selectivity filter carboxylates are not protonated. The pH-independent current helps to protect activation of skeletal muscle during the acidosis that occurs during exercise.
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Registered trials
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.