Activation of the action potential Na+ ionophore by neurotoxins. An allosteric model.

The alkaloid neurotoxins aconitine, veratridine, grayanotoxin, and batrachotoxin activate the action potential Na+ ionophore by interaction with a common binding site. Concentration-response curves are fit by simple Langmuir isotherms. The fraction of Na+ ionophores activated at saturating concentrations of neurotoxin are: aconitine, 0.02; veratridine, 0.08; grayanotoxin, 0.51; and batrachotoxin, 0.95. The concentrations required to obtain 50% of the maximum activation are: aconitine, 3.6 x 10m6 M; veratridine, 2.9 X 10ms M; grayanotoxin, 1.2 x 1O-3 M; and batrachotoxin, 7.0 X It7 M. Incubation of cells with scorpion toxin causes an increase in the fraction of Na+ ionophores activated at saturating concentrations of alkaloid toxins (P,) and a decrease in the concentration required to obtain 50% of maximum activation (K,,,): aconitine, P, = 0.21, Ko.5 = 2.7 x 10m6 M; veratridine, P, = 0.56, Ko.s = 1.5 x 1O-5 M; grayanotoxin, P, = 0.96, K,,, = 9.2 x 10m5 M; batrachotoxin, P, = 1.0, K,., = 5.2 x 10-S M. For the partial activators, the primary effect of scorpion toxin is to increase P,. For the full activators, the primary effect of scorpion toxin is to decrease K,,.5. In each case the concentration response curves are fit by a simple Langmuir isotherm with a Hill coefficient of 1.0. An allosteric mode1 is presented which describes the activation of the Na+ ionophore by alkaloid toxins and the heterotropic cooperative effect of scorpion toxin. In this model, the Na+ ionophore is assumed to exist in two states, active and inactive. Alkaloid toxins activate the ionophore by binding preferentially to the active state. Scorpion toxin enhances activation by alkaloid toxins by altering the equilibrium constant (allosteric constant) for the transition between the active and inactive states.

• Publication year

  1977

• Venue

  Journal of Biological Chemistry

• Publication date

  Unknown publication date

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0021-9258(19)75273-9PMID 925017
• 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.

• Membrane potential-dependent binding of scorpion toxin to the action potential Na+ ionophore. Studies with a toxin derivative prepared by lactoperoxidase-catalyzed iodination.

  1977cited by this paper
• Purification of a toxic protein from scorpion venom which activates the action potential Na+ ionophore.

  1976cited by this paper
• Activation and inhibition of the action potential Na+ ionophore of cultured rat muscle cells by neurotoxins.

  1976cited by this paper
• Kinetic and pharmacological properties of the sodium channel of frog skeletal muscle

  1976cited by this paper
• Membrane potential dependent binding of scorpion toxin to action potential Na+ ionophore.

  1976cited by this paper
• Correlation of surface antigens and cell type in cloned cell lines from the rat central nervous system.

  1976cited by this paper
• Sodium currents in voltage clamped nerve fiber of frog under the combined action of batrachotoxin and procaine.

  1975cited by this paper
• Activation of the action potential Na+ ionophore of cultured neuroblastoma cells by veratridine and batrachotoxin.

  1975cited by this paper
• Cooperative activation of action potential Na+ ionophore by neurotoxins.

  1975cited by this paper
• The receptor for tetrodotoxin and saxitoxin. A structural hypothesis.

  1975cited by this paper
• Modification of sodium channel gating in frog myelinated nerve fibres by Centruroides sculpturatus scorpion venom.

  1975cited by this paper
• Effect of aconitine on the sodium permeability of the node of ranvier

  1974cited by this paper
• Gating Currents of the Sodium Channels: Three Ways to Block Them

  1974cited by this paper
• Evidence that tetrodotoxin and saxitoxin act at a metal cation binding site in the sodium channels of nerve membrane.

  1974cited by this paper
• Mechanism of nerve membrane depolarization caused by grayanotoxin I

  1974cited by this paper
• Increase in sodium permeability of squid axon membranes by -dihydrograyanotoxin II.

  1973cited by this paper
• Sodium uptake associated with activation of action potential ionophores of cultured neuroblastoma and muscle cells.

  1973cited by this paper
• Tetrodotoxin and cobalt blockade of neuroblastoma action potentials.

  1973cited by this paper
• Characterization of batrachotoxin-induced depolarization of the squid giant axons.

  1973cited by this paper
• Biophysics and Physiology of Excitable Membranes

  1973cited by this paper
• Inactivation of the Sodium Current in Myxicola Giant Axons

  1972cited by this paper
• Effects of scorpion venom on squid axon membranes.

  1972cited by this paper
• The pharmacology of batrachotoxin. IV. Interaction with tetrodotoxin on innervated and chronically denervated rat skeletal muscle.

  1972cited by this paper
• Electrogenesis in mouse neuroblastoma cells In vitro

  1971cited by this paper
• Batrachotoxin: Chemistry and Pharmacology

  1971cited by this paper
• Genes for neuronal properties expressed in neuroblastoma x L cell hybrids.

  1971cited by this paper
• Neuronal tumor cells with excitable membranes grown in vitro.

  1969cited by this paper
• [Effect of scorpion venom on ionic currents of the node of Ranvier. I. The permeabilities PNa and PK].

  1968cited by this paper
• On the excitability and cooperativity of the electroplax membrane.

  1968cited by this paper
• On the application of "a plausible model" of allosteric proteins to the receptor for acetylcholine.

  1967cited by this paper
• Comparison of experimental binding data and theoretical models in proteins containing subunits.

  1966cited by this paper
• ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.

  1965cited by this paper
• From the U. S. A.

  1965cited by this paper
• Tetrodotoxin Blockage of Sodium Conductance Increase in Lobster Giant Axons

  1964cited by this paper
• The Effect of Aconitine on the Giant Axon of the Squid

  1964cited by this paper
• The kinetics of enzyme-catalyzed reactions with two or more substrates or products. II. Inhibition: nomenclature and theory.

  1963cited by this paper
• A quantitative description of membrane current and its application to conduction and excitation in nerve

  1952cited by this paper
• Protein measurement with the Folin phenol reagent.

  1951cited by this paper
• The effect of sodium ions on the electrical activity of the giant axon of the squid

  1949cited by this paper

• Batrachotoxin Sensitive Sodium Channels in Toxic Birds Challenge “Target Mutation” Strategy of Toxin Autoresistance

  2026cites this paper
• Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin

  2024cites this paper
• Therapeutic targeting of voltage-gated sodium channel NaV1.7 for cancer metastasis

  2024cites this paper
• Divergent Synthetic Approach to Grayanane Diterpenoids.

  2023cites this paper
• Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist

  2022cites this paper
• Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases

  2022influential citation
• Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins

  2021cites this paper
• Veratridine: A Janus-Faced Modulator of Voltage-Gated Sodium Ion Channels.

  2020cites this paper
• Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs

  2020cites this paper
• Extensive literature search on grayanotoxins and 5‐hydroxymethylfurfural

  2020cites this paper
• Serotherapy against Voltage-Gated Sodium Channel-Targeting α-Toxins from Androctonus Scorpion Venom

  2019cites this paper
• Targeted profiling and relative quantification of benzoyl diterpene alkaloids in Aconitum roots by using LC-MS/MS with precursor ion scan.

  2018cites this paper
• Inhibition of veratridine-induced delayed inactivation of the voltage-sensitive sodium channel by synthetic analogs of crambescin B.

  2017cites this paper
• The management of ventricular dysrhythmia in aconite poisoning

  2017cites this paper
• Inhibition of Sodium Ion Channel Function with Truncated Forms of Batrachotoxin.

  2016cites this paper
• Characterization of Interaction Between Brevetoxin and Its Native Receptor and Identification of the Role of Brevetoxin in Karenia brevis

  2016influential citation
• Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV

  2016cites this paper
• Modification of α subunit of RIIA sodium channels by aconitine

  2014cites this paper
• Molecular Studies of Alpha-Scorpion Toxin Interactions with Voltage-gated Sodium Channels

  2012cites this paper
• Synthesis and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as potent sodium channel blockers for the treatment of stroke.

  2012cites this paper
• Pharmacokinetics of aconitine in rat skin after oral and transdermal gel administrations.

  2012cites this paper
• Channels as Enzymes: Oxymoron and Tautology

  2011cites this paper
• Cell Culture in the Neurosciences

  2011cites this paper
• Acceleration of Ion Diffusion Due to the Electromagnetic Effects of Ion Currents in Nanochannels

  2011cites this paper
• Identification of New Batrachotoxin-sensing Residues in Segment IIIS6 of the Sodium Channel*

  2011cites this paper
• Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

  2011cites this paper
• Update of risk assessments of main marine biotoxins in the European Union.

  2011cites this paper
• Binding of sodium channel inhibitors to hyperpolarized and depolarized conformations of the channel.

  2011cites this paper
• Modification of Na Channels by Synthetic Dihydrobatrachotoxinin A-20 «-Benzoate

  2010cites this paper
• Investigation of mutagenic effects of Grayanotoxins II and III on cultured human lymphocytes.

  2010cites this paper
• Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 alpha subunits

  2010cites this paper
• Development of a novel HPLC-MS/MS method for the determination of aconitine and its application to in vitro and rat microdialysis samples.

  2009cites this paper
• Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria.

  2009cites this paper
• Influence of Lipid-Soluble Gating Modifier Toxins on Sodium Influx in Neocortical Neurons

  2008cites this paper
• α-Scorpion Toxin Impairs a Conformational Change that Leads to Fast Inactivation of Muscle Sodium Channels

  2008cites this paper
• Site-3 sea anemone toxins: molecular probes of gating mechanisms in voltage-dependent sodium channels.

  2007cites this paper
• Voltage-gated ion channels and gating modifier toxins.

  2007cites this paper
• Voltage-gated sodium channel toxins

  2007cites this paper
• Historical and current perspectives of neuroactive compounds derived from Latin America.

  2006cites this paper
• Functional characterization of sodium channel blockers by membrane potential measurements in cerebellar neurons: prediction of compound preference for the open/inactivated state.

  2006cites this paper
• Natural products from ginseng inhibit [3H]batrachotoxinin A 20-alpha-benzoate binding to Na+ channels in mammalian brain.

  2006cites this paper
• Sodium channel activators: Model of binding inside the pore and a possible mechanism of action

  2005cites this paper
• Properties of the interaction of the sodium channel with permeant monovalent cations.

  2005cites this paper
• Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.

  2004cites this paper
• Antagonism by Local Anesthetics of Sodium Channel Activators in the Presence of Scorpion Toxins: Two Mechanisms for Competitive Inhibition

  2004cites this paper
• Potential-dependent action ofAnemonia sulcata toxins III and IV on sodium channels in crayfish giant axons

  2004cites this paper
• Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the voltage-gated Na+ channel.

  2003cites this paper
• State‐dependent access to the batrachotoxin receptor on the sodium channel

  2003cites this paper
• Relationship between lamotrigine oral dose, serum level and its inhibitory effect on CNS: insights from transcranial magnetic stimulation.

  2003cites this paper
• Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins.

  2003cites this paper
• The autocrine excitotoxicity of antillatoxin, a novel lipopeptide derived from the antropical [sic] marine cyanobacterium Lyngbya majuscula

  2003cites this paper
• BARNES AND HILLE Sodium Channel Modification by Veratridine 423 coated with Sylgard

  2003cites this paper
• Variations in receptor site-3 on rat brain and insect sodium channels highlighted by binding of a funnel-web spider delta-atracotoxin.

  2002cites this paper
• Rapid and functional neurobiochemical assays for marine algal toxins using mouse brain synaptoneurosomes

  2002cites this paper
• The batrachotoxin receptor on the voltage-gated sodium channel is guarded by the channel activation gate.

  2002influential citation
• Comparison of aconitine‐modified human heart (hH1) and rat skeletal (μ1) muscle Na+ channels: an important role for external Na+ ions

  2002cites this paper
• Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Cavβ subunits

  2001cites this paper
• Effect of depolarization on binding kinetics of scorpion alpha-toxin highlights conformational changes of rat brain sodium channels.

  2001cites this paper
• Chemotransduction properties of nodose ganglion cardiac afferent neurons in guinea pigs.

  2000cites this paper
• Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.

  2000cites this paper
• Ion channel modifying agents influence the electrical activity generated by canine intrinsic cardiac neurons in situ.

  2000cites this paper
• Modification of alpha subunit of RIIA sodium channels by aconitine.

  2000cites this paper
• Voltage-dependent gating of veratridine-modified RIIA Na+ channel α subunit expressed heterologously in CHO cells

  1999cites this paper
• An nmr conformational analysis of a synthetic peptide Cn2(1-15)NH2-S-S-acetyl-Cn2(52-66)NH2 from the New World Centruroides noxius 2 (Cn2) scorpion toxin: comparison of the structure with those of the Centruroides scorpion toxins.

  1999cites this paper
• Augmentation of Recovery from Inactivation by Site-3 Na Channel Toxins

  1999cites this paper
• Immune‐mediated peripheral neuropathies and voltage‐gated sodiums channels

  1999cites this paper
• Effect of Grayanotoxin II on In Vitro Mitotic Activity of Human Lymphocytes

  1998cites this paper
• Delta-atracotoxins from Australian funnel-web spiders compete with scorpion alpha-toxin binding on both rat brain and insect sodium channels.

  1998cites this paper
• Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel.

  1998cites this paper
• Similarities between vasoconstrictor- and veratridine-stimulated metabolism in perfused rat hind limb.

  1998cites this paper
• delta-Atracotoxins from australian funnel-web spiders compete with scorpion alpha-toxin binding but differentially modulate alkaloid toxin activation of voltage-gated sodium channels.

  1998cites this paper
• Depolarization Differentially Affects Allosteric Modulation by Neurotoxins of Scorpion α‐Toxin Binding on Voltage‐Gated Sodium Channels

  1998cites this paper
• Pharmacological characterization of Na+ influx via voltage-gated Na+ channels in spinal cord astrocytes.

  1997cites this paper
• Solution structures of a highly insecticidal recombinant scorpion alpha-toxin and a mutant with increased activity.

  1997cites this paper
• Toxin III from Leiurus quinquestriatus quinquestriatus: a specific probe for receptor site 3 on insect sodium channels.

  1997cites this paper
• Effects of grayanotoxin-I on threshold intensity and compound action potential of frog sciatic nerve.

  1996cites this paper
• Alpha-scorpion toxins binding on rat brain and insect sodium channels reveal divergent allosteric modulations by brevetoxin and veratridine.

  1996cites this paper
• Effects of besipirdine at the voltage‐dependent sodium channel

  1995cites this paper
• Monoclonal Antibodies against Noxiustoxin

  1995cites this paper
• Dilazep inhibits binding of batrachotoxin to sodium channels in canine sarcolemmal vesicles.

  1995cites this paper
• Cloning and characterization of the cDNAs encoding Na+ channel-specific toxins 1 and 2 of the scorpion Centruroides noxius Hoffmann.

  1995cites this paper
• Mechanism of thiamine transport in neuroblastoma cells. Inhibition of a high affinity carrier by sodium channel activators and dependence of thiamine uptake on membrane potential and intracellular ATP.

  1994cites this paper
• Class I antiarrhythmic drugs: allosteric inhibitors of [3H] batrachotoxinin binding to rat cardiac sodium channels.

  1994cites this paper
• Cloning and characterization of cDNAs that code for Na(+)-channel-blocking toxins of the scorpion Centruroides noxius Hoffmann.

  1993cites this paper
• Specific binding of the novel Na+ channel blocker PD85,639 to the alpha subunit of rat brain Na+ channels.

  1993cites this paper
• Gating and conductance in an outward-rectifying K+ channel from the plasma membrane of Saccharomyces cerevisiae

  1993cites this paper
• Differences in the neuroexcitatory actions of pyrethroid insecticides and sodium channel-specific neurotoxins in rat and trout brain synaptosomes.

  1993cites this paper
• Mutually exclusive action of cationic veratridine and cevadine at an intracellular site of the cardiac sodium channel

  1992cites this paper
• Cellular and molecular biology of voltage-gated sodium channels.

  1992cites this paper
• Interaction of pumiliotoxin B with an "alkaloid-binding domain" on the voltage-dependent sodium channel.

  1992cites this paper
• Amino acid sequence and immunological characterization with monoclonal antibodies of two toxins from the venom of the scorpion Centruroides noxius Hoffmann.

  1992cites this paper
• Properties of veratridine-modified single Na+ channels in guinea pig ventricular myocytes.

  1992cites this paper
• Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells

  1992cites this paper
• Grayanotoxin-I-modified eel electroplax sodium channels. Correlation with batrachotoxin and veratridine modifications

  1992influential citation
• BTX modification of Na channels in squid axons. I. State dependence of BTX action

  1991cites this paper
• Supersensitivity to tetrodotoxin and lignocaine of sea anemone toxin II‐treated sodium channel in guinea‐pig ventricular muscle

  1991cites this paper
• Seronegative myasthenia gravis: A plasma factor inhibiting agonist‐induced acetylcholine receptor function copurifies with IgM

  1991cites this paper
• Inactivation modifiers of Na+ currents and the gating of rat brain Na+ channels in planar lipid membranes

  1991cites this paper
• Effect of structural modification of several groups on the D-ring of grayanotoxin on its depolarization potency in squid giant axon.

  1991cites this paper
• A preferential inhibition of impulses in C-fibers of the rabbit vagus nerve by veratridine, an activator of sodium channels.

  1990cites this paper