ArticleThe Journal of physiology2004
Accessibility of mid-segment domain IV S6 residues of the voltage-gated Na+ channel to methanethiosulfonate reagents.
Article in The Journal of physiology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Inhibition of Sodium Ion Channel Function with Truncated Forms of Batrachotoxin.ACS chemical neuroscience · 2016Article
- Congruent pattern of accessibility identifies minimal pore gate in a non-symmetric voltage-gated sodium channel.Nature communications · 2016Article
- Important Role of Asparagines in Coupling the Pore and Votage-Sensor Domain in Voltage-Gated Sodium Channels.Biophysical journal · 2015Article
- Evolutionarily conserved intracellular gate of voltage-dependent sodium channels.Nature communications · 2014Article
- Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel.Nature communications · 2013Article
- Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block.Cellular and molecular life sciences : CMLS · 2012Review
- Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels.Nature communications · 2011Article
- Molecular determinants of state-dependent block of voltage-gated sodium channels by pilsicainide.British journal of pharmacology · 2010Article
- A homology model of the pore domain of a voltage-gated calcium channel is consistent with available SCAM data.The Journal of general physiology · 2010Article
- Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.Circulation research · 2009Article
- The external pore loop interacts with S6 and S3-S4 linker in domain 4 to assume an essential role in gating control and anticonvulsant action in the Na(+) channel.The Journal of general physiology · 2009Article
- The activation gate and gating mechanism of the NMDA receptor.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2008Article
- Charge at the lidocaine binding site residue Phe-1759 affects permeation in human cardiac voltage-gated sodium channels.The Journal of physiology · 2007Article
- Isoform-dependent interaction of voltage-gated sodium channels with protons.The Journal of physiology · 2006Article
- Slow sodium channel inactivation and use-dependent block modulated by the same domain IV S6 residue.The Journal of membrane biology · 2005Article
- Tryptophan substitution of a putative D4S6 gating hinge alters slow inactivation in cardiac sodium channels.Biophysical journal · 2005Article
- Physiological and pharmacologic aspects of peripheral nerve blocks.Journal of anaesthesiology, clinical pharmacologyArticle
- A molecular model of the inner pore of the Ca channel in its open state.Channels (Austin, Tex.)Article
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Authors and funding
6 authors.
Funding
Abstract
The inner pore of the voltage-gated Na+ channel is predicted by the structure of bacterial potassium channels to be lined with the four S6 alpha-helical segments. Our previously published model of the closed pore based on the KcsA structure, and our new model of the open pore based on the MthK structure predict which residues in the mid-portion of S6 face the pore. We produced cysteine mutants of the mid-portion of domain IV-S6 (Ile-1575-Leu-1591) in NaV 1.4 and tested their accessibility to intracellularly and extracellularly placed positively charged methanethiosulfonate (MTS) reagents. We found that only two mutants, F1579C and V1583C, were accessible to both outside and inside 2-(aminoethyl)-methanethiosulfonate hydrobromide (MTSEA) Further study of those mutants showed that efficient closure of the fast inactivation gate prevented block by inside [2-(trimethylammonium)ethyl]methanethiosulfonate bromide (MTSET) at slow stimulation rates. When fast inactivation was inhibited by exposure to anthropleurin B (ApB), increasing channel open time, both mutants were blocked by inside MTSET at a rate that depended on the amount of time the channel was open. Consistent with the fast inactivation gate limiting access to the pore, in the absence of ApB, inside MTSET produced block when the cells were stimulated at 5 or 20 Hz. We therefore suggest that the middle of IV-S6 is an alpha-helix, and we propose a model of the open channel, based on MthK, in which Phe-1579 and Val-1583 face the pore.
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