Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.
Mu-conotoxins are a family of peptides from the venoms of predatory cone snails. Previously characterized mu-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, mu-conotoxin SmIIIA from Conus stercusmuscarum. Although mu-conotoxin SmIIIA shares several biochemical characteristics with other mu-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 mu-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.
West
Peter J
PJ
Interdepartmental Program in Neuroscience and Department of Biology, University of Utah, Salt Lake City, Utah 84112, USA.
Bulaj
Grzegorz
G
Garrett
James E
JE
Olivera
Baldomero M
BM
Yoshikami
Doju
D
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D020916:Conotoxins / Q000138:chemical synthesis / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D004351:Drug Resistance; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D011894:Rana pipiens; D012908:Snails; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*
D020916:Conotoxins; D010455:Peptides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C470785:mu-conotoxin SmIIIA; D013779:Tetrodotoxin