-Conotoxin PIA Is Selective for6 Subunit-Containing Nicotinic Acetylcholine Receptors

Until now, there have been no antagonists to discriminate between heteromeric nicotinic acetylcholine receptors (nAChRs) containing the very closely related 6 and 3 subunits. nAChRs containing 3, 4, or 6 subunits in combination with 2, occasionally 4, and sometimes 3o r5 subunits, are thought to play important roles in cognitive function, pain perception, and the reinforcing properties of nicotine. We cloned a novel gene from the predatory marine snail Conus purpurascens. The predicted peptide, -conotoxin PIA, potently blocks the chimeric 6/323 subunit combination as expressed in oocytes but neither the muscle nor the major neuronal nAChR 42. Additionally, this toxin is the first described ligand to discriminate between nAChRs containing 6 and 3 subunits. Exploiting the unusual intron conservation of conotoxin genes may represent a more general approach for defining conotoxin ligand scaffolds to discriminate among closely related receptor populations.