Molecular mechanisms of neurotoxin action on voltage-gated sodium channels
Introduction
Sodium channels are transmembrane proteins responsible for the voltage-dependent increase in sodium permeability that initiates action potentials [1]. Sodium channels consist of a pore forming α subunit of 260 kDa associated with auxiliary subunits: β1, β2 and β3 [2], [3], [4], [5]. The α subunit consists of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6), and one reentrant segment (SS1/SS2) connected by internal and external polypeptide loops (figure 1A) [2], [6]. The S4 segments are positively charged and serve as voltage sensors to initiate the voltage-dependent activation of sodium channels by moving outward under the influence of the electric field (figure 1A) [7], [8], [9]. Inactivation is mediated by the short intracellular loop connecting domains III and IV (figure 1A) [8], [10], [11]. The membrane-reentrant loops between S5 and S6 (SS1-SS2) form the ion selectivity filter and the outer region of the pore (figure 1A) [12], [13], [14].
Sodium channels are the molecular target for several groups of neurotoxins, which strongly alter channel function by binding to specific receptor sites. Due to their high affinity and specificity, neurotoxins represent powerful tools to study the structure and the function of sodium channels, affecting both permeation and gating properties of the channel. Therefore, localization of the neurotoxin receptor sites gives unique information on the structure-function relationships of the sodium channel. Six different receptor sites have been identified on voltage-dependent sodium channels using different neurotoxins. Here, we have reviewed the sites and mechanisms of action of six different classes of neurotoxins that act on sodium channels.
Section snippets
Neurotoxin receptor sites
Early pharmacological studies of sodium channels led to the conclusion that neurotoxins act at four distinct receptor sites and have primary effects on either ion permeation or voltage-dependent gating (table I) [15], [16]. Subsequent studies provided evidence for site 5 [17], [18] and site 6 [19]. The receptor sites at which neurotoxins affect gating were found to be allosterically coupled, suggesting that conformational changes induced by neurotoxin binding alter the equilibrium between the
Pore-blocking toxins
Receptor site 1 on sodium channels is occupied by two different groups of toxins: the water soluble heterocyclic guanidines tetrodotoxin (TTX) and saxitoxin (STX) and the peptidic μ-contoxins. All of these toxins act from the extracellular side of the membrane. TTX is isolated from the tissues of at least 40 species of puffer fish [21], but it is also found in molluscs, crabs, octopus, and Central American frogs [22], [23], [24]. STX is produced by the marine dinoflagellate Gonyaulax catenella
Neurotoxin receptor site 2
Lipid-soluble grayanotoxins (found in rhododendron and other plants of the family Ericaceae), the alkaloids veratridine (from of Liliaceae), acotinine (from the plant Acotinum napellus) and batrachotoxin (from the skin of the Colombian frog Phyllobates aurotaenia) bind to receptor site 2. These toxins bind preferentially to the activated state of sodium channels and cause persistent activation at resting membrane potential via an allosteric mechanism that leads to block of sodium channel
Neurotoxin receptor site 3
Neurotoxin receptor site 3 of sodium channels is occupied by several groups of polypeptide toxins: α-scorpion toxins, sea-anemone toxins and some spider toxins. These toxins slow or block sodium channel inactivation [30], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66].
Alpha-scorpion toxins are a family of structurally and functionally related polypeptides neurotoxins, each containing 60 to 70 amino acid residues cross-linked by four disulfide bonds [67], [68]. They have been
Molecular mechanisms of neurotoxin action on ion channels
From the extensive studies reviewed above, the molecular mechanisms of action of neurotoxins on sodium channels can be divided into three classes: pore block, indirect allosteric modulation of gating, and voltage-sensor trapping. These three mechanisms are considered below.
References (111)
- et al.
Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif
Cell
(1995) - et al.
Molecular basis of charge movement in voltage-gated sodium channels
Neuron
(1996) - et al.
A single point mutaion confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II
FEBS Lett.
(1989) - et al.
Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II
FEBS Lett.
(1991) - et al.
A new neurotoxin receptor site on sodium channels is identified by a conotoxin that affects sodium channel inactivation in molluscs and acts as an antagonist in rat brain
J. Biol. Chem.
(1994) Activation of the action potential Na+ ionophore by neurotoxins. An allosteric model
J. Biol. Chem.
(1977)- et al.
Occurrence of tetrodotoxin in the frog Atelopus oxyrhynchus
Toxicon
(1989) - et al.
Tetrodotoxin and derivatives in several species of the gastropod Naticidae
Toxicon
(1991) - et al.
Conus geographus toxins that discriminate between neuronal and muscle sodium channels
J. Biol. Chem.
(1985) The receptor site for tetrodotoxin and saxitoxin. A structural hypothesis
Biophys. J.
(1975)
Geographutoxin II, a peptide sodium channel blocker that selectively inhibits [3H] saxitoxin binding to muscle and nerve sodium channels
J. Biol. Chem.
Blockade of [3H] lysine-tetrodotoxin binding to sodium channel proteins by conotoxin GIII
Neurosci. Lett.
A μ-conotoxin-insensitive Na+ channel mutant: possible localization of a binding site at the outer vestibule
Biophys. J.
Extrapore residues of the S5-S6 loop of domain 2 of the voltage-gated skeletal muscle sodium channel (rSkM1) contribute to the mu-conotoxin GIIIA binding site
Biophys. J.
Site of covalent labeling by a photoreactive batrachotoxin derivative near transmembrane segment IS6 of the sodium channel alpha subunit
J. Biol. Chem.
Batrachotoxin-resistant Na+ channels derived from point mutations in transmembrane segment D4-S6
Biophys. J.
On site of action of grayanotoxin in domain 4 segment 6 of rat skeletal muscle sodium channel
FEBS Lett.
Effects of ciguatoxin on current and voltage clamped frog myelinated nerve fibre
Toxicon
Ciguatoxin and brevetoxins share a common receptor site on the neuronal voltage-dependent Na+ channel
FEBS Lett.
Decreased rate of sodium conductance inactivation in the nodes of Ranvier induced by polypeptide toxin from sea anemone
Biochim. Biophys. Acta
The voltage-dependent Na+ channel of insect nervous system identified by receptor sites for tetrodotoxin, and scorpion and sea anemone toxins
Biochem. Biophys. Res. Commun.
Scorpion venoms and neurotoxins: an immunological study
Toxicon
Binding of scorpion and sea anemone neurotoxins to a common site related to the action potential Na+ ionophore in neuroblastoma cells
Biochem. Biophys. Res. Commun.
Binding of an α scorpion toxin to insect sodium channels is not dependent on membrane potential
FEBS Lett.
Toxin III from Leiurus quinquestriatus quinquestriatus: a specific probe for receptor site 3 on insect sodium channels
Insect Biochem. Mol. Biol.
Binding of scorpion toxin to receptor sites associated with voltage-sensitive sodium channels in synaptic nerve ending particles
J. Biol. Chem.
Two types of scorpion neurotoxins characterized by their binding to two separate receptor sites on rat brain synaptosomes
Biochem. Biophys. Res. Commun.
Alpha-scorpion toxins binding on rat brain and insect sodium channels reveal divergent allosteric modulations by brevetoxin and veratridine
J. Biol. Chem.
Sea anemone toxin and scorpion toxin share a common receptor site associated with the action potential ionophore
J. Biol. Chem.
Scorpion toxins affecting sodium current inactivation bind to distinct homologous receptor sites on rat brain and insect sodium channels
J. Biol. Chem.
Importance of the unique cationic residues arginine 12 and lysine 49 in the activity of the cardiotonic polypeptide anthopleurin B
J. Biol. Chem.
Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit
J. Biol. Chem.
A specific interaction between the cardiac sodium channel and site-3 toxin anthopleurin B
J. Biol. Chem.
The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4
Biophys. J.
Voltage sensor-trapping: enhanced activation of sodium channels by beta-scorpion toxin bound to the S3-S4 loop in domain II
Neuron
A quantitative description of membrane current and its application to conduction and excitation in nerves
J. Physiol.
Cellular and molecular biology of voltage-dependent sodium channels
Physiol. Rev.
Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel
Science
Beta 3: An additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics
Proc. Natl. Acad. Sci. USA
Existence of distinct sodium channel messenger RNAs in rat brain
Nature
Sodium channels and gating currents
Physiol. Rev.
Structural parts involved in activation and inactivation of sodium channel
Nature
Identification of an intracellular peptide segment involved in sodium channel inactivation
Science
A cluster of hydrophobic amino acid residues required for fast Na+ channel inactivation
Proc. Natl. Acad. Sci. USA
Calcium channel characteristics conferred on the sodium channel by single mutations
Nature
Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes
Annu. Rev. Pharmacol. Toxicol.
Scorpion neurotoxins: effects and mechanisms
Toxin T46 from Ptychodiscus brevis (formely Gymnodinium breve) enhances activation of voltage-sensitive sodium channels by veratridine
Mol. Pharmacol.
Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat vrain synaptosones
Mol. Pharmacol.
Tetrodotoxin.
Sci. Am.
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Current address: CNRS-UMR 6560, Université de la Mediterranée, IFR Jean Roche, 13916 Marseille, France