Novel Conotoxins from Conus striatus and Conus kinoshitai Selectively Block TTX-Resistant Sodium Channels

• Published in: Biochemistry (Easton) Vol. 44; no. 19; pp. 7259 - 7265
• Main Authors: Bulaj, Grzegorz, West, Peter J, Garrett, James E, Watkins, Maren, Zhang, Min-Min, Norton, Raymond S, Smith, Brian J, Yoshikami, Doju, Olivera, Baldomero M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.05.2005
• Subjects: Action Potentials - drug effects; Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; Conotoxins - chemistry; Conotoxins - isolation & purification; Conotoxins - pharmacology; Female; Ganglia, Spinal - chemistry; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Ganglia, Sympathetic - chemistry; Ganglia, Sympathetic - drug effects; Ganglia, Sympathetic - metabolism; Male; Molecular Sequence Data; Mollusk Venoms - chemistry; Mollusk Venoms - isolation & purification; Mollusk Venoms - pharmacology; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Neuropeptides - antagonists & inhibitors; Neuropeptides - metabolism; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Rana pipiens; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - isolation & purification; Sodium Channel Blockers - pharmacology; Sodium Channels - metabolism; Tetrodotoxin - chemistry; Tetrodotoxin - pharmacology
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi0473408

The peptides isolated from venoms of predatory marine Conus snails (“conotoxins”) are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, μ-conotoxins SIIIA and KIIIA, from two species of cone snails. The two toxins were identified and characterized by combining molecular techniques and chemical synthesis. Both peptides inhibit TTX-resistant sodium currents in neurons of frog sympathetic and dorsal root ganglia but poorly block action potentials in frog skeletal muscle, which are mediated by TTX-sensitive sodium channels. The amino acid sequences in the C-terminal region of the two peptides and of the previously characterized μ-conotoxin SmIIIA (which also blocks TTX-resistant channels) are similar, but the three peptides differ in the length of their first N-terminal loop. We used molecular dynamics simulations to analyze how altering the number of residues in the first loop affects the overall structure of μ-conotoxins. Our results suggest that the naturally occurring truncations do not affect the conformation of the C-terminal loops. Taken together, structural and functional differences among μ-conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the “evolutionary engineering” of conotoxin activity.