The Outer Vestibule of the Na+ Channel–Toxin Receptor and Modulator of Permeation as Well as Gating

The outer vestibule of voltage-gated Na+ channels is formed by extracellular loops connecting the S5 and S6 segments of all four domains (“P-loops”), which fold back into the membrane. Classically, this structure has been implicated in the control of ion permeation and in toxin blockage. However, conformational changes of the outer vestibule may also result in alterations in gating, as suggested by several P-loop mutations that gave rise to gating changes. Moreover, partial pore block by mutated toxins may reverse gating changes induced by mutations. Therefore, toxins that bind to the outer vestibule can be used to modulate channel gating.

• Publication year

  2010

• Venue

  Marine Drugs

• Publication date

  2010-04-21

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3390/md8041373PMID 20479982PMCID 2866490
• 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.

• Structural basis for the coupling between activation and inactivation gates in K+ channels

  2010cited by this paper
• An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

  2010cited by this paper
• 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

  2009cited by this paper
• Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

  2009cited by this paper
• Structural Basis For The Coupling Between Activation And Inactivation Gating In Potassium Channels

  2009cited by this paper
• Cardiac Ion Channel Gene Mutations in Sudden Infant Death Syndrome

  2008influential reference
• Interaction between voltage-gated sodium channels and the neurotoxin, tetrodotoxin

  2008influential reference
• Speeding the recovery from ultraslow inactivation of voltage-gated Na+ channels by metal ion binding to the selectivity filter: a foot-on-the-door?

  2007cited by this paper
• Principles underlying energetic coupling along an allosteric communication trajectory of a voltage-activated K+ channel

  2007cited by this paper
• The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Na(v1.6) voltage-dependent sodium channel.

  2007cited by this paper
• Partial expression defect for the SCN5A missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine.

  2006influential reference
• Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C.

  2006cited by this paper
• How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis

  2006cited by this paper
• Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR

  2006cited by this paper
• A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation

  2006cited by this paper
• Tryptophan substitution of a putative D4S6 gating hinge alters slow inactivation in cardiac sodium channels.

  2005cited by this paper
• Novel Brugada syndrome-causing mutation in ion-conducting pore of cardiac Na+ channel does not affect ion selectivity properties.

  2005cited by this paper
• Electrostatic recognition and induced fit in the kappa-PVIIA toxin binding to Shaker potassium channel.

  2005cited by this paper
• International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels

  2005cited by this paper
• Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.

  2005cited by this paper
• International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

  2005cited by this paper
• Inherited disorders of voltage-gated sodium channels.

  2005cited by this paper
• Use-dependent block with tetrodotoxin and saxitoxin at frog Ranvier nodes I. Intrinsic channel and toxin parameters

  2005cited by this paper
• Single point mutations of the sodium channel drastically reduce the pore permeability without preventing its gating

  2005cited by this paper
• Brugada syndrome: report of the second consensus conference.

  2005cited by this paper
• Sodium channel inactivation: molecular determinants and modulation.

  2005cited by this paper
• Use-dependent block with tetrodotoxin and saxitoxin at frog Ranvier nodes II. Extrinsic influence of cations

  2005cited by this paper
• A multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptor.

  2004cited by this paper
• Lidocaine: a foot in the door of the inner vestibule prevents ultra-slow inactivation of a voltage-gated sodium channel.

  2004cited by this paper
• Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death.

  2004cited by this paper
• Binding of κ-Conotoxin PVIIA to Shaker K+ Channels Reveals Different K+ and Rb+ Occupancies within the Ion Channel Pore

  2004cited by this paper
• Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach.

  2004cited by this paper
• Tonic and phasic guanidinium toxin-block of skeletal muscle Na channels expressed in Mammalian cells.

  2003cited by this paper
• Interaction between Fast and Ultra-slow Inactivation in the Voltage-gated Sodium Channel

  2002cited by this paper
• Modeling the structure of agitoxin in complex with the Shaker K+ channel: a computational approach based on experimental distance restraints extracted from thermodynamic mutant cycles.

  2002cited by this paper
• Mutation D384N Alters Recovery of the Immobilized Gating Charge in Rat Brain IIA Sodium Channels

  2002cited by this paper
• Slow Inactivation Does Not Block the Aqueous Accessibility to the Outer Pore of Voltage-gated Na Channels

  2002cited by this paper
• Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block

  2002cited by this paper
• A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease.

  2002cited by this paper
• Energetics of pore opening in a voltage-gated K(+) channel.

  2002cited by this paper
• Role of Amino Acid Residues in Transmembrane Segments IS6 and IIS6 of the Na+ Channel α Subunit in Voltage-dependent Gating and Drug Block*

  2002cited by this paper
• The Selectivity Filter of the Voltage-gated Sodium Channel Is Involved in Channel Activation*

  2001cited by this paper
• Residue-specific effects on slow inactivation at V787 in D2-S6 of Na(v)1.4 sodium channels.

  2001cited by this paper
• Clockwise Domain Arrangement of the Sodium Channel Revealed by μ-Conotoxin (GIIIA) Docking Orientation*

  2001cited by this paper
• A single residue differentiates between human cardiac and skeletal muscle Na+ channel slow inactivation.

  2001cited by this paper
• Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution

  2001cited by this paper
• KcsA crystal structure as framework for a molecular model of the Na(+) channel pore.

  2000cited by this paper
• A point mutation in domain 4-segment 6 of the skeletal muscle sodium channel produces an atypical inactivation state.

  2000cited by this paper
• A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome

  2000cited by this paper
• A Structural Rearrangement in the Sodium Channel Pore Linked to Slow Inactivation and Use Dependence

  2000cited by this paper
• The voltage sensor in voltage-dependent ion channels.

  2000cited by this paper
• Rapid and slow voltage-dependent conformational changes in segment IVS6 of voltage-gated Na(+) channels.

  2000cited by this paper
• μ-Conotoxin Giiia Interactions with the Voltage-Gated Na+ Channel Predict a Clockwise Arrangement of the Domains

  2000cited by this paper
• Molecular Dynamics of the Sodium Channel Pore Vary with Gating: Interactions between P-Segment Motions and Inactivation

  1999cited by this paper
• The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4.

  1999cited by this paper
• Enhanced slow inactivation by V445M: a sodium channel mutation associated with myotonia.

  1999cited by this paper
• Tonic and phasic tetrodotoxin block of sodium channels with point mutations in the outer pore region.

  1999cited by this paper
• Ultra-slow inactivation in mu1 Na+ channels is produced by a structural rearrangement of the outer vestibule.

  1999cited by this paper
• Differences in saxitoxin and tetrodotoxin binding revealed by mutagenesis of the Na+ channel outer vestibule.

  1998cited by this paper
• Predominant interactions between mu-conotoxin Arg-13 and the skeletal muscle Na+ channel localized by mutant cycle analysis.

  1998cited by this paper
• The structure of the potassium channel: molecular basis of K+ conduction and selectivity.

  1998cited by this paper
• Inactivation of voltage-gated cardiac K+ channels.

  1998cited by this paper
• Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat μ1 skeletal muscle sodium channel

  1998cited by this paper
• Slow inactivation in human cardiac sodium channels.

  1998cited by this paper
• Sodium channel selectivity filter regulates antiarrhythmic drug binding.

  1997influential reference
• A mutation in segment I-S6 alters slow inactivation of sodium channels.

  1997cited by this paper
• Molecular motions within the pore of voltage-dependent sodium channels.

  1997cited by this paper
• Sodium Channel Activation Gating Is Affected by Substitutions of Voltage Sensor Positive Charges in All Four Domains

  1997cited by this paper
• A unique role for the S4 segment of domain 4 in the inactivation of sodium channels

  1996cited by this paper
• Two conformational states involved in the use-dependent TTX blockade of human cardiac Na+ channel.

  1996influential reference
• The guanidinium toxin binding site on the sodium channel.

  1996cited by this paper
• Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.

  1996cited by this paper
• External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels.

  1996cited by this paper
• Use dependence of tetrodotoxin block of sodium channels: a revival of the trapped-ion mechanism.

  1996cited by this paper
• Interactions between a pore-blocking peptide and the voltage sensor of the sodium channel: an electrostatic approach to channel geometry.

  1996cited by this paper
• A mu-conotoxin-insensitive Na+ channel mutant: possible localization of a binding site at the outer vestibule.

  1995cited by this paper
• A mutation in the pore of the sodium channel alters gating.

  1995cited by this paper
• A structural model of the tetrodotoxin and saxitoxin binding site of the Na+ channel.

  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
• Post-repolarization block of cloned sodium channels by saxitoxin: the contribution of pore-region amino acids.

  1994cited by this paper
• Post-repolarization block of cardiac sodium channels by saxitoxin.

  1993influential reference
• Site-directed mutagenesis of the putative pore region of the rat IIA sodium channel.

  1993cited by this paper
• Action of derivatives of mu-conotoxin GIIIA on sodium channels. Single amino acid substitutions in the toxin separately affect association and dissociation rates.

  1992cited by this paper
• Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel.

  1992cited by this paper
• Calcium channel characteristics conferred on the sodium channel by single mutations

  1992cited by this paper
• A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.

  1992cited by this paper
• A Mutant of TTX-Resistant Cardiac Sodium Channels with TTX-Sensitive Properties

  1992cited by this paper
• The effect of tetrodotoxin on the sodium gating current in the squid giant axon

  1991cited by this paper
• A voltage-dependent gating transition induces use-dependent block by tetrodotoxin of rat IIA sodium channels expressed in Xenopus oocytes.

  1991influential reference
• Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II

  1991cited by this paper
• Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels.

  1991cited by this paper
• Use dependence of sodium current inhibition by tetrodotoxin in rat cardiac muscle: influence of channel state

  1990cited by this paper
• Beta 1 subunits of sodium channels. Studies with subunit-specific antibodies.

  1990cited by this paper
• Inactivation of cloned Na channels expressed in Xenopus oocytes

  1990cited by this paper
• A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II

  1989cited by this paper
• Structural parts involved in activation and inactivation of the sodium channel

  1989cited by this paper
• Use-dependent block of sodium channels in frog myelinated nerve by tetrodotoxin and saxitoxin at negative holding potentials.

  1989cited by this paper
• Evidence for voltage-dependent block of cardiac sodium channels by tetrodotoxin.

  1988cited by this paper
• Slow sodium channel inactivation in mammalian muscle: A possible role in regulating excitability

  1988cited by this paper

• Functional effects of drugs and toxins interacting with NaV1.4

  2024cites this paper
• Trifunctional Saxitoxin Conjugates for Covalent Labeling of Voltage‐Gated Sodium Channels **

  2023cites this paper
• In Silico Analysis of Tetrodotoxin Binding in Voltage-Gated Sodium Ion Channels from Toxin-Resistant Animal Lineages

  2022cites this paper
• Characterization of Compound-Specific, Concentration-Independent Biophysical Properties of Sodium Channel Inhibitor Mechanism of Action Using Automated Patch-Clamp Electrophysiology

  2021cites this paper
• Structural pharmacology of voltage-gated sodium channels.

  2021cites this paper
• Tetrodotoxin: Geschichte, Biologie und Synthese

  2019cites this paper
• Tetrodotoxin: History, Biology, and Synthesis.

  2019cites this paper
• Convergent and parallel evolution in a voltage-gated sodium channel underlies TTX-resistance in the Greater Blue-ringed Octopus: Hapalochlaena lunulata.

  2019cites this paper
• Progress in understanding slow inactivation speeds up

  2018cites this paper
• Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.

  2017cites this paper
• A pharmacological and transcriptomic approach to exploring novel pain targets

  2016cites this paper
• Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses

  2015cites this paper
• Chronic Toxicity Study of Neosaxitoxin in Rats

  2014cites this paper
• Use-dependent block of the voltage-gated Na+ channel by tetrodotoxin and saxitoxin: Effect of pore mutations that change ionic selectivity

  2012cites this paper
• Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

  2011cites this paper