A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI.
We report the isolation, characterization, and total synthesis of a small peptide ligand for nicotinic acetylcholine receptors (nAChRs). It is highly active against the neuromuscular receptor in frog but not in mice. In contrast, it induces seizures when injected centrally in mice and rats, suggesting that it may target neuronal nAChRs in mammals. Although such receptors may be important in both normal cognition and the pathophysiology of several neuropsychiatric disorders, there are few ligands to discriminate between the multiple receptor subtypes. The new peptide is a highly divergent alpha-conotoxin from the snail Conus imperialis, which preys on polychaete worms. In this article, the purification, structural analysis, synthesis, and preliminary physiological characterization of alpha-conotoxin ImI (alpha-CTx-ImI) are reported. The sequence of the peptide is: Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2. The peptide shows striking sequence differences from all alpha-conotoxins of fish-hunting Conus, but its disulfide-bridging is similar: [2-8; 3-12]. We suggest that cone venoms may provide an array of ligands with selectivity for various neuronal nAChR subtypes.
McIntosh
J M
JM
Department of Psychiatry, University of Utah, Salt Lake City 84112.
Yoshikami
D
D
Mahe
E
E
Nielsen
D B
DB
Rivier
J E
JE
Gray
W R
WR
Olivera
B M
BM
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D002217:Carbachol / Q000494:pharmacology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D020916:Conotoxins; D004220:Disulfides / Q000032:analysis; D004555:Electric Fish; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000737:chemistry*; D009045:Motor Endplate / Q000187:drug effects / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000633:toxicity; D011894:Rana pipiens; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D012908:Snails
D020916:Conotoxins; D004220:Disulfides; D008024:Ligands; D008978:Mollusk Venoms; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011978:Receptors, Nicotinic; C087686:alpha-conotoxin ImI; D002217:Carbachol