μ-Conotoxin SmIIIA, a Potent Inhibitor of Tetrodotoxin-Resistant Sodium Channels in Amphibian Sympathetic and Sensory Neurons

Abstract

μ-Conotoxins are a family of peptides from the venoms of predatory cone snails. Previously characterized μ-conotoxins preferentially block skeletal muscle voltage-gated sodium channels. We report here the discovery (via cloning), synthesis, and electrophysiological characterization of a new peptide in this family, μ-conotoxin SmIIIA from Conus stercusmuscarum. Although μ-conotoxin SmIIIA shares several biochemical characteristics with other μ-conotoxins (the arrangement of cysteine residues and a conserved arginine believed to interact with residues near the channel pore), it has distinctive features such as the absence of hydroxyproline. In voltage-clamped dissociated neurons from frog sympathetic and dorsal root ganglia, the peptide inhibited the majority of tetrodotoxin-resistant sodium currents irreversibly; in contrast, tetrodotoxin-sensitive sodium currents were largely unaffected by the peptide. We believe that μ-conotoxin SmIIIA is the first specific antagonist of tetrodotoxin-resistant voltage-gated sodium channels to be discovered. Thus, the peptide provides a new and potentially useful tool to investigate the functional roles of tetrodotoxin-resistant voltage-gated sodium channels, including those that are found in sensory nerves that convey nociceptive information.