Marine Toxins That Target Voltage-gated Sodium Channels

Abstract

Eukaryotic, voltage-gated sodium (Na V ) channels are large membrane proteins which underlie generation and propagation of rapid electrical signals in nerve, muscle and heart. Nine different Na V receptor sites, for natural ligands and/or drugs, have been identified, based on functional analyses and site-directed mutagenesis. In the marine ecosystem, numerous toxins have evolved to disrupt Na V channel function, either by inhibition of current flow through the channels, or by modifying the activation and inactivation gating processes by which the channels open and close. These toxins function in their native environment as offensive or defensive weapons in prey capture or deterrence of predators. In composition, they range from organic molecules of varying size and complexity to peptides consisting of ~10-70 amino acids. We review the variety of known Na V -targeted marine toxins, outlining, where known, their sites of interaction with the channel protein and their functional effects. In a number of cases, these natural ligands have the potential applications as drugs in clinical settings, or as models for drug development.

Interactions of Key Charged Residues Contributing to Selective Block of Neuronal Sodium Channels by μ-Conotoxin KIIIA

“…To date, nine mammalian Na v channels have been described (Na v 1.1-1.9) (Catterall et al, 2005;Al-Sabi et al, 2006); these have differing distributions throughout the body. Gain-of-function mutations in Na v channels causing hyperexcitability, have been linked to such disease states as cardiac arrhythmia (Wang et al, 1995), epilepsy (Escayg et al, 2000), myotonia (Cannon, 1997), and pain (Waxman et al, 1999).…”

NaVβ Subunits Modulate the Inhibition of NaV1.8 by the Analgesic Gating Modifier μO-Conotoxin MrVIB

“…Many of the more recently discovered ligands that target VGSCs are components of animal venoms (Al-Sabi et al, 2006;Billen et al, 2008). The peptide toxins from cone snail venoms are a particularly rich source (Terlau and Olivera, 2004), and at least four families of conopeptides target VGSCs, each via a different mechanism: -conotoxins, like the action of TTX and STX, block the channel's pore (Catterall et al, 2007); O-conotoxins are gating modifiers that block channel activation (Zorn et al, 2006;Heinemann and Leipold, 2007;Leipold et al, 2007); -conotoxins promote channel activation (Fiedler et al, 2008); and ␦-conotoxins inhibit fast inactivation (Leipold et al, 2005;West et al, 2005).…”

Orientation of μ-Conotoxin PIIIA in a Sodium Channel Vestibule, Based on Voltage Dependence of Its Binding

“…-Conotoxins (CTXs) show striking isoform selectivity among different Na v channels. CTXs inhibit current through Na v channels by binding to toxin site 1 in the outer vestibule of the channel [for an overview of Na v channel binding sites, see Catterall et al (2005) and Al-Sabi et al (2006)]. Studies of toxin binding provide opportunities both to probe the architecture of the sodium channel outer vestibule and also to study the selectivity of the toxins.…”