ArticleBiophysical journal1997
Mechanisms of sodium/calcium selectivity in sodium channels probed by cysteine mutagenesis and sulfhydryl modification.
Article in Biophysical journal, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
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- Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Mechanical and cellular processes driving cervical myelopathy.World journal of orthopedics · 2016Review
- Reporting sodium channel activity using calcium flux: pharmacological promiscuity of cardiac Nav1.5.Molecular pharmacology · 2015Article
- Structural basis for the selective permeability of channels made of communicating junction proteins.Biochimica et biophysica acta · 2013Review
- Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Biophysical costs associated with tetrodotoxin resistance in the sodium channel pore of the garter snake, Thamnophis sirtalis.Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology · 2011Article
- Voltage-gated Na channel selectivity: the role of the conserved domain III lysine residue.The Journal of general physiology · 2008Review
- An inactivation stabilizer of the Na+ channel acts as an opportunistic pore blocker modulated by external Na+.The Journal of general physiology · 2005Article
- Compound-specific Na+ channel pore conformational changes induced by local anaesthetics.The Journal of physiology · 2005Article
- Block of tetrodotoxin-resistant Na+ channel pore by multivalent cations: gating modification and Na+ flow dependence.The Journal of general physiology · 2004Article
- Influence of pore residues on permeation properties in the Kv2.1 potassium channel. Evidence for a selective functional interaction of K+ with the outer vestibule.The Journal of general physiology · 2003Article
- The cation selectivity filter of the bacterial sodium channel, NaChBac.The Journal of general physiology · 2002Article
- Effect of Na(+) flow on Cd(2+) block of tetrodotoxin-resistant Na(+) channels.The Journal of general physiology · 2002Article
- A genetically targetable fluorescent probe of channel gating with rapid kinetics.Biophysical journal · 2002Article
- Molecular architecture of the voltage-dependent Na channel: functional evidence for alpha helices in the pore.The Journal of general physiology · 2001Article
- mu-conotoxin GIIIA interactions with the voltage-gated Na(+) channel predict a clockwise arrangement of the domains.The Journal of general physiology · 2000Article
- Differences in saxitoxin and tetrodotoxin binding revealed by mutagenesis of the Na+ channel outer vestibule.Biophysical journal · 1998Article
- Structure and function of voltage-gated sodium channels.The Journal of physiology · 1998Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
A conserved lysine residue in the "P loop" of domain III renders sodium channels highly selective. Conversion of this residue to glutamate, to mimic the homologous position in calcium channels, enables Ca2+ to permeate sodium channels. Because the lysine-to-glutamate mutation converts a positively charged side chain to a negative one, it has been proposed that a positive charge at this position suffices for Na+ selectivity. We tested this idea by converting the critical lysine to cysteine (K1237C) in mu 1 rat skeletal sodium channels expressed in Xenopus oocytes. Selectivity of the mutant channels was then characterized before and after chemical modification to alter side-chain charge. Wild-type channels are highly selective for Na+ over Ca2+ (PCa/PNa < 0.01). The K1237C mutation significantly increases permeability to Ca2+ (PCa/PNa = 0.6) and Sr2+. Analogous mutations in domains I (D400C), II (E755C), and IV (A1529C) did not alter the selectivity for Na+ over Ca2+, nor did any of the domain IV mutations (G1530C, W1531C, and D1532C) that are known to affect monovalent selectivity. Interestingly, the increase in permeability to Ca2+ in K1237C cannot be reversed by simply restoring the positive charge to the side chain by using the sulfhydryl modifying reagent methanethiosulfonate ethylammonium. Single-channel studies confirmed that modified K1237C channels, which exhibit a reduced unitary conductance, remain permeable to Ca2+, with a PCa/PNa of 0.6. We conclude that the chemical identity of the residue at position 1237 is crucial for channel selectivity. Simply rendering the 1237 side chain positive does not suffice to restore selectivity to the channel.
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