Novel excitatory Conus peptides define a new conotoxin superfamily

• Published in: Journal of neurochemistry 2003-05, Vol.85 (3), p.610-621
• Main Authors: Jimenez, Elsie C., Shetty, Reshma P., Lirazan, Marcelina, Rivier, Jean, Walker, Craig, Abogadie, Fe C., Yoshikami, Doju, Cruz, Lourdes J., Olivera, Baldomero M.
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Amphibia; Animals; Biological and medical sciences; Biological Assay; conotoxins; Conotoxins - genetics; Conotoxins - isolation & purification; Conotoxins - pharmacology; Conus radiatus; Electrophysiology; excitotoxins; frog electrophysiology; Fundamental and applied biological sciences. Psychology; Gene Library; gene superfamilies; General aspects. Models. Methods; Goldfish; In Vitro Techniques; Mice; Mollusk Venoms - chemistry; Multigene Family; Muscle, Skeletal - drug effects; Muscle, Skeletal - innervation; Muscle, Skeletal - physiology; Neurotoxins - genetics; Neurotoxins - isolation & purification; Neurotoxins - pharmacology; Peptides - genetics; Peptides - isolation & purification; Peptides - pharmacology; peripheral axons; Peripheral Nerves - drug effects; Peripheral Nerves - physiology; Rana pipiens; repetitive action potentials; Sequence Analysis, Protein; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01685.x

A new class of Conus peptides, the I‐superfamily of conotoxins, has been characterized using biochemical, electrophysiological and molecular genetic methods. Peptides in this superfamily have a novel pattern of eight Cys residues. Five peptides that elicited excitatory symptomatology, r11a, r11b, r11c, r11d and r11e, were purified from Conus radiatus venom; four were tested on amphibian peripheral axons and shown to elicit repetitive action potentials, consistent with being members of the ‘lightning‐strike cabal’ of toxins that effect instant immobilization of fish prey. A parallel analysis of Conus cDNA clones revealed a new class of conotoxin genes that was particularly enriched (with 18 identified paralogues) in a Conus radiatus venom duct library; several C. radiatus clones encoded the excitatory peptides directly characterized from venom. The remarkable diversity of related I‐superfamily peptides within a single Conus species is unprecedented. When combined with the excitatory effects observed on peripheral circuitry, this unexpected diversity suggests a corresponding molecular complexity of the targeted signaling components in peripheral axons; the I‐conotoxin superfamily should provide a rich lode of pharmacological tools for dissecting and understanding these. Thus, the I‐superfamily conotoxins promise to provide a significant new technology platform for dissecting the molecular components of axons.