A unique role for the S4 segment of domain 4 in the inactivation of sodium channels

Sodium channels have four homologous domains (D1-D4) each with six putative transmembrane segments (S1-S6). The highly charged S4 segments in each domain are postulated voltage sensors for gating. We made 15 charge-neutralizing or -reversing substitutions in the first or third basic residues (arginine or lysine) by replacement with histidine, glutamine, or glutamate in S4 segments of each domain of the human heart Na+ channel. Nine of the mutations cause shifts in the conductance-voltage (G-V) midpoints, and all but two significantly decrease the voltage dependence of peak Na+ current, consistent with a role of S4 segments in activation. The decreases in voltage dependence of activation were equivalent to a decrease in apparent gating charge of 0.5-2.1 elementary charges (eo) per channel for single charge- neutralizing mutations. Three charge-reversing mutations gave decreases of 1.2-1.9 eo per channel in voltage dependence of activation. The steady-state inactivation (h infinity) curves were fit by single- component Boltzmann functions and show significant decreases in slope for 9 of the 15 mutants and shifts of midpoints in 9 mutants. The voltage dependence of inactivation time constants is markedly decreased by mutations only in S4D4, providing further evidence that this segment plays a unique role in activation-inactivation coupling.

• Publication year

  1996

• Venue

  The Journal of General Physiology

• Publication date

  1996-12-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1085/JGP.108.6.549PMID 8972392PMCID 2229343
• 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.

• Gating of sodium and potassium channels

  2005cited by this paper
• Molecular basis of charge movement in voltage-gated sodium channels.

  1996cited by this paper
• Role of an S4-S5 linker in sodium channel inactivation probed by mutagenesis and a peptide blocker

  1996cited by this paper
• Direct Physical Measure of Conformational Rearrangement Underlying Potassium Channel Gating

  1996cited by this paper
• Electrostatic interactions of S4 voltage sensor in Shaker K+ channel.

  1995cited by this paper
• A molecular link between activation and inactivation of sodium channels

  1995cited by this paper
• Evidence for voltage-dependent S4 movement in sodium channels.

  1995cited by this paper
• Differential effects of sulfhydryl reagents on saxitoxin and tetrodotoxin block of voltage-dependent Na channels.

  1994cited by this paper
• Effects of III-IV linker mutations on human heart Na+ channel inactivation gating.

  1994cited by this paper
• Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation.

  1994cited by this paper
• The kinetics of voltage-gated ion channels

  1994cited by this paper
• Voltage gating of ion channels

  1994cited by this paper
• Na+ channels must deactivate to recover from inactivation.

  1994cited by this paper
• S4 mutations alter gating currents of Shaker K channels.

  1994cited by this paper
• Point mutations in IIS4 alter activation and inactivation of rat brain IIA Na channels in Xenopus oocyte macropatches

  1994cited by this paper
• Gating charge differences between two voltage-gated K+ channels are due to the specific charge content of their respective S4 regions.

  1993cited by this paper
• The size of gating charge in wild-type and mutant Shaker potassium channels.

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

  1992cited by this paper
• Incremental reductions of positive charge within the S4 region of a voltage-gated K+ channel result in corresponding decreases in gating charge.

  1992cited by this paper
• Chimeric study of sodium channels from rat skeletal and cardiac muscle

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

  1992cited by this paper
• Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.

  1992cited by this paper
• Molecular kinetics of voltage-dependent Na+ channels.

  1991influential reference
• A role for hydrophobic residues in the voltage-dependent gating of Shaker K+ channels.

  1991cited by this paper
• Alteration of voltage-dependence of Shaker potassium channel by mutations in the S4 sequence

  1991cited by this paper
• Voltage-sensing residues in the S4 region of a mammalian K+ channel

  1991cited by this paper
• Hydrophobic substitution mutations in the S4 sequence alter voltage-dependent gating in Shaker K+ channels.

  1991influential reference
• Changes in sodium channel gating produced by point mutations in a cytoplasmic linker.

  1990cited by this paper
• A neutral amino acid change in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel.

  1990cited by this paper
• Structural parts involved in activation and inactivation of the sodium channel

  1989cited by this paper
• Molecular diversity of voltage-sensitive Na channels.

  1989cited by this paper
• Inactivation viewed through single sodium channels

  1984cited by this paper
• A reinterpretation of mammalian sodium channel gating based on single channel recording

  1983cited by this paper
• Sodium channels and gating currents.

  1981cited by this paper

• Differential Inhibition by Cenobamate of Canonical Human Nav1.5 Ion Channels and Several Point Mutants

  2025cites this paper
• SCN5A missense variants and their contribution to deaths in Sudden Unexplained Nocturnal Death Syndrome (SUNDS).

  2025cites this paper
• The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.

  2025cites this paper
• Elucidating the roles of voltage sensors in NaV1.9 activation and inactivation through a spider toxin.

  2025cites this paper
• Structure-function and pharmacologic aspects of ion channels relevant to neurologic channelopathies.

  2024cites this paper
• Inhibitory Effects of Cenobamate on Multiple Human Cardiac Ion Channels and Possible Arrhythmogenic Consequences

  2024cites this paper
• An artificial intelligence accelerated virtual screening platform for drug discovery

  2024cites this paper
• Structural biology and molecular pharmacology of voltage-gated ion channels

  2024cites this paper
• ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS

  2024influential citation
• Inactivation of the Kv2.1 channel through electromechanical coupling

  2023cites this paper
• Complex biophysical changes and reduced neuronal firing in an SCN8A variant associated with developmental delay and epilepsy

  2023cites this paper
• Closed-state inactivation of cardiac, skeletal, and neuronal sodium channels is isoform specific

  2022cites this paper
• Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation

  2021cites this paper
• Seizure Phenotype and Underlying Cellular Defects in Drosophila Knock-In Models of DS (R1648C) and GEFS+ (R1648H) SCN1A Epilepsy

  2021cites this paper
• Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome

  2021cites this paper
• Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits

  2021cites this paper
• Induced Pluripotent Stem Cell-Derived Cardiomyocytes with SCN5A R1623Q Mutation Associated with Severe Long QT Syndrome in Fetuses and Neonates Recapitulates Pathophysiological Phenotypes

  2021cites this paper
• Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study

  2020cites this paper
• Deep Mutational Scan of an SCN5A Voltage Sensor

  2020cites this paper
• Cav2.3 channel function and Zn2+-induced modulation: potential mechanisms and (patho)physiological relevance

  2020cites this paper
• Variable patterns of mutation density among NaV1.1, NaV1.2 and NaV1.6 point to channel-specific functional differences associated with childhood epilepsy

  2020cites this paper
• Deep Mutational Scan of a cardiac sodium channel voltage sensor

  2019cites this paper
• Structural basis of α-scorpion toxin action on Nav channels

  2019cites this paper
• Aus dem Zentrum Neurologie Neurologische Universitätsklinik Tübingen Hertie-Institut für klinische Hirnforschung Abteilung Neurologie mit Schwerpunkt Epileptologie Functional studies of mutations in SCN2A gene associated with early-onset epilepsy

  2019cites this paper
• Distinct modulation of inactivation by a residue in the pore domain of voltage-gated Na+ channels: mechanistic insights from recent crystal structures

  2018cites this paper
• A quantized physical framework for understanding the working mechanism of ion channels

  2018cites this paper
• A perspective on Na and K channel inactivation

  2018cites this paper
• Voltage-Gated Sodium Channels and Electrical Excitability of the Heart

  2018cites this paper
• Isopimaric acid – a multi‐targeting ion channel modulator reducing excitability and arrhythmicity in a spontaneously beating mouse atrial cell line

  2018cites this paper
• NaV Channels: Assaying Biosynthesis, Trafficking, Function.

  2018cites this paper
• Mechanisms of Drug Binding to Voltage-Gated Sodium Channels.

  2018cites this paper
• Using voltage‐sensor toxins and their molecular targets to investigate NaV1.8 gating

  2018cites this paper
• Gating currents

  2018cites this paper
• GAGA Factor Expedites Development in Drosophila

  2017cites this paper
• Pharmacology of the Nav1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

  2017cites this paper
• Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density

  2017cites this paper
• Transepithelial delivery of macromolecular biopesticides

  2017cites this paper
• Annotation of functional impact of voltage‐gated sodium channel mutations

  2017cites this paper
• Multi-scale modeling and variability in cardiac cellular electrophysiology

  2017cites this paper
• Molecular interaction of δ-conopeptide EVIA with voltage-gated Na(+) channels.

  2016cites this paper
• SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel.

  2016cites this paper
• The hitchhiker’s guide to the voltage-gated sodium channel galaxy

  2016cites this paper
• A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.

  2016cites this paper
• Nav Channels in Damaged Membranes.

  2016cites this paper
• Fast-onset lidocaine block of rat NaV1.4 channels suggests involvement of a second high-affinity open state.

  2016cites this paper
• Derivation of Hodgkin-Huxley equations for a Na^{+} channel from a master equation for coupled activation and inactivation.

  2016cites this paper
• Evolution of voltage-gated ion channels at the emergence of Metazoa

  2015influential citation
• Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na+ Channels

  2015cites this paper
• Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome

  2015cites this paper
• Nav1.5 mutations linked to dilated cardiomyopathy phenotypes

  2014cites this paper
• 1 – Voltage-Gated Sodium Channels and Electrical Excitability of the Heart

  2014cites this paper
• Gating-Pore Currents Demonstrate Selective and Specific Modulation of Individual Sodium Channel Voltage-Sensors by Biological Toxins

  2014cites this paper
• Brugada Syndrome Disease Phenotype Explained in Apparently Benign Sodium Channel Mutations

  2014cites this paper
• The voltage sensor module in sodium channels.

  2014cites this paper
• Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

  2014cites this paper
• Probing gating mechanisms of sodium channels using pore blockers.

  2014cites this paper
• A gating model for wildtype and R1448H Nav1.4 channels in paramyotonia

  2014cites this paper
• Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.

  2014cites this paper
• S1–S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation

  2013cites this paper
• Charakterisierung neuer Hypokaliämische Periodische Paralysen verursachender Mutationen in Domäne III des spannungsabhängigen Natriumkanals 1.4 mit Hilfe der Patch-clamp Technik

  2013cites this paper
• Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel

  2013cites this paper
• Correction: S1–S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation

  2013cites this paper
• What activates inactivation?

  2013cites this paper
• Outward stabilization of the voltage sensor in domain II but not domain I speeds inactivation of voltage-gated sodium channels.

  2013influential citation
• Direct Evidence that Scorpion α-Toxins (Site-3) Modulate Sodium Channel Inactivation by Hindrance of Voltage-Sensor Movements

  2013cites this paper
• Domain IV voltage-sensor movement is both sufficient and rate limiting for fast inactivation in sodium channels

  2013cites this paper
• Etude des sous-unités auxiliaires du canal sodium dépendant du potentiel d'insecte : Approches moléculaires, électrophysiologiques et pharmacologiques

  2013cites this paper
• A gating charge interaction required for late slow inactivation of the bacterial sodium channel NavAb

  2013cites this paper
• Effects of cysteine mutations in the S 4S 5 linkers from domains D 1 to D 4 on the fast inactivation of the voltage-gated sodium channel

  2013cites this paper
• The basis for calcium regulation of the cardiac sodium channel

  2012cites this paper
• Domain III regulates N-type (CaV2.2) calcium channel closing kinetics.

  2012cites this paper
• The Unique Role of the Domain IV Voltage-Sensor in Sodium Channel Inactivation and Gating

  2012cites this paper
• Modulation of neuronal sodium channels by the sea anemone peptide BDS-I.

  2012cites this paper
• Open- and closed-state fast inactivation in sodium channels

  2011cites this paper
• Polyunsaturated Fatty Acids Modifying Ion Channel Voltage Gating

  2011cites this paper
• Differential resistance of insect sodium channels with kdr mutations to deltamethrin, permethrin and DDT.

  2011cites this paper
• Couplage entre les régions IIS4-S5 et IIS6 lors de l'activation du canal calcique CaV2.3

  2011cites this paper
• Alternative splicing in SCN1A : biophysical consequences for NaV1.1 channels

  2011cites this paper
• Impaired stretch modulation in potentially lethal cardiac sodium channel mutants

  2010influential citation
• The sea anemone Bunodosoma caissarum toxin BcIII modulates the sodium current kinetics of rat dorsal root ganglia neurons and is displaced in a voltage-dependent manner.

  2010cites this paper
• Phyla- and Subtype-Selectivity of CgNa, a Na+ Channel Toxin from the Venom of the Giant Caribbean Sea Anemone Condylactis Gigantea

  2010cites this paper
• SCN5A Rare Variants in Familial Dilated Cardiomyopathy Decrease Peak Sodium Current Depending on the Common Polymorphism H558R and Common Splice Variant Q1077del

  2010cites this paper
• The Outer Vestibule of the Na+ Channel–Toxin Receptor and Modulator of Permeation as Well as Gating

  2010cites this paper
• The Timothy syndrome mutation of cardiac CaV1.2 (L‐type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation

  2009influential citation
• 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

  2009cites this paper
• Local Anesthetics Disrupt Energetic Coupling between the Voltage-sensing Segments of a Sodium Channel

  2009cites this paper
• Studies of α-Helicity and Intersegmental Interactions in Voltage-Gated Na+ Channels: S2D4

  2009cites this paper
• Erythromelalgia mutation L823R shifts activation and inactivation of threshold sodium channel Nav1.7 to hyperpolarized potentials.

  2009cites this paper
• Dilated cardiomyopathy due to sodium channel dysfunction: what is the connection?

  2008cites this paper
• Peptide toxins that selectively target insect NaV and CaV channels

  2008cites this paper
• Electrophysiological characterization of BmK I, an alpha-like scorpion toxin, on rNav1.5 expressed in HEK293t cells.

  2008cites this paper
• Differential effects of paramyotonia congenita mutations F1473S and F1705I on sodium channel gating

  2008cites this paper
• Investigating the Role of a Cation Channel-like Protein NCA-1 in Regulating Synaptic Activity and Development in Caenorhabditis elegans

  2008cites this paper
• SCN5A channelopathies--an update on mutations and mechanisms.

  2008cites this paper
• Biophysical defects in voltage-gated sodium channels associated with Long QT and Brugada syndromes

  2008cites this paper
• Homozygous SCN5A mutation in Brugada syndrome with monomorphic ventricular tachycardia and structural heart abnormalities.

  2007cites this paper
• The insecticidal potential of scorpion β-toxins

  2007cites this paper
• Conotoxins of the O-superfamily affecting voltage-gated sodium channels

  2007cites this paper
• NA+‐ and K+‐channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres

  2007cites this paper
• The effect of the outermost basic residues in the S4 segments of the CaV3.1 T-type calcium channel on channel gating

  2007influential citation