The Na+ Channel Inactivation Gate Is a Molecular Complex

Electrical activity in nerve, skeletal muscle, and heart requires finely tuned activity of voltage-gated Na+ channels that open and then enter a nonconducting inactivated state upon depolarization. Inactivation occurs when the gate, the cytoplasmic loop linking domains III and IV of the α subunit, occludes the open pore. Subtle destabilization of inactivation by mutation is causally associated with diverse human disease. Here we show for the first time that the inactivation gate is a molecular complex consisting of the III-IV loop and the COOH terminus (C-T), which is necessary to stabilize the closed gate and minimize channel reopening. When this interaction is disrupted by mutation, inactivation is destabilized allowing a small, but important, fraction of channels to reopen, conduct inward current, and delay cellular repolarization. Thus, our results demonstrate for the first time that physiologically crucial stabilization of inactivation of the Na+ channel requires complex interactions of intracellular structures and indicate a novel structural role of the C-T domain in this process.

• Publication year

  2004

• Venue

  The Journal of General Physiology

• Publication date

  2004-02-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1085/jgp.200308929PMID 14744988PMCID 2217430
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Molecular basis of inherited epilepsy.

  2004cited by this paper
• Sodium channels SCN1A, SCN2A and SCN3A in familial autism

  2003cited by this paper
• Common Molecular Determinants of Flecainide and Lidocaine Block of Heart Na+ Channels

  2003influential reference
• Non-Equilibrium Gating in Cardiac Na+ Channels: An Original Mechanism of Arrhythmia

  2003cited by this paper
• Local Structure Prediction with Local Structure-based Sequence Profiles

  2003influential reference
• Defective cardiac ion channels: from mutations to clinical syndromes.

  2002cited by this paper
• A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction.

  2002cited by this paper
• Secondary Structure of the Human Cardiac Na+ Channel C Terminus

  2002influential reference
• Molecular modeling and dynamics of the sodium channel inactivation gate.

  2002cited by this paper
• Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation

  2002cited by this paper
• Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation

  2002cited by this paper
• Local structure-based sequence profile database for local and global protein structure predictions

  2002influential reference
• Molecular basis of an inherited epilepsy.

  2002cited by this paper
• Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide

  2002influential reference
• Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.

  2002influential reference
• Role of the C-terminal domain in inactivation of brain and cardiac sodium channels

  2001cited by this paper
• Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel

  2001cited by this paper
• A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities.

  2001cited by this paper
• Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.

  2001cited by this paper
• Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome

  2001cited by this paper
• Molecular and cellular mechanisms of cardiac arrhythmias.

  2001cited by this paper
• From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.

  2000influential reference
• Two distinct congenital arrhythmias evoked by a multidysfunctional Na(+) channel.

  2000cited by this paper
• Biophysical phenotypes of SCN5A mutations causing long QT and Brugada syndromes

  2000influential reference
• Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.

  1999cited by this paper
• Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia

  1999cited by this paper
• A single Na(+) channel mutation causing both long-QT and Brugada syndromes.

  1999cited by this paper
• Block of Brain Sodium Channels by Peptide Mimetics of the Isoleucine, Phenylalanine, and Methionine (IFM) Motif from the Inactivation Gate

  1999cited by this paper
• Solution structure of the sodium channel inactivation gate.

  1999influential reference
• Kinetic Analysis of Block of Open Sodium Channels by a Peptide Containing the Isoleucine, Phenylalanine, and Methionine (IFM) Motif from the Inactivation Gate

  1998cited by this paper
• A Critical Role for the S4-S5 Intracellular Loop in Domain IV of the Sodium Channel α-Subunit in Fast Inactivation*

  1998influential reference
• Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

  1997cited by this paper
• Movement of the Na+ Channel Inactivation Gate during Inactivation*

  1996influential reference
• A hypothetical structural role for proline residues in the flanking segments of protein-protein interaction sites.

  1995cited by this paper
• A Critical Role for Transmembrane Segment IVS6 of the Sodium Channel α Subunit in Fast Inactivation (*)

  1995cited by this paper
• Molecular mechanism for an inherited cardiac arrhythmia

  1995influential reference
• A mutation in segment IVS6 disrupts fast inactivation of sodium channels.

  1994influential reference
• CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.

  1994cited by this paper
• Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro.

  1994cited by this paper
• Phosphorylation of a conserved protein kinase C site is required for modulation of Na+ currents in transfected Chinese hamster ovary cells.

  1992influential reference
• A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.

  1992influential reference
• Amino acid residues required for fast Na(+)-channel inactivation: charge neutralizations and deletions in the III-IV linker.

  1992cited by this paper
• Structural parts involved in activation and inactivation of the sodium channel

  1989cited by this paper
• Common Molecular Determinants of Flecainide and Lidocaine Block of Heart Na (cid:2) Channels: Evidence from Experiments with Neutral and Quaternary Flecainide Analogues

  year unknowninfluential reference

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• Subcellular diversity of Nav1.5 in cardiomyocytes: distinct functions, mechanisms and targets

  2022cites this paper
• Sodium Channelopathies of Skeletal Muscle and Brain.

  2021cites this paper
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  2021cites this paper
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  2020cites this paper
• E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, disrupts sodium channel inactivation through two separate mechanisms

  2020cites this paper
• Supramolecular clustering of the cardiac sodium channel Nav1.5 in HEK293F cells, with and without the auxiliary β3‐subunit

  2020cites this paper
• The cardiac CaMKII-Nav1.5 relationship: From physiology to pathology.

  2020cites this paper
• Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5

  2020cites this paper
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  2020cites this paper
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  2019cites this paper
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  2019cites this paper
• Effects of FGF14 and NaVβ4 deletion on transient and resurgent Na current in cerebellar Purkinje neurons

  2019cites this paper
• Detection of Nav1.5 Conformational Change in Mammalian Cells Using the Noncanonical Amino Acid ANAP.

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• Physiological and pharmacological switches combine to uniquely modulate the most common cardiac sodium channel mutant, E1784K

  2018influential citation
• Development of a genetically encoded site-specific fluorescent sensor of human cardiac voltage-gated sodium channel inactivation

  2018cites this paper
• Predicting changes to INa from missense mutations in human SCN5A

  2018cites this paper
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  2018cites this paper
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• Cardiac Sodium Channel (Dys)Function and Inherited Arrhythmia Syndromes

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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
• Proton modulation of residue E1784 and its regulation of fast inactivation

  2017cites this paper
• Molecular Pathophysiology of Congenital Long QT Syndrome.

  2017cites this paper
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  2017cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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• Sodium channels, cardiac arrhythmia, and therapeutic strategy.

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• Calcium Alleviates Symptoms in Hyperkalemic Periodic Paralysis by Reducing the Abnormal Sodium Influx

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• Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies

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• Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block

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• Pathophysiology of the cardiac late Na current and its potential as a drug target.

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• The basis for calcium regulation of the cardiac sodium channel

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