α-Conotoxin PIA Is Selective for α6 Subunit-Containing Nicotinic Acetylcholine Receptors

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Abstract
Until now, there have been no antagonists to discriminate between heteromeric nicotinic acetylcholine receptors (nAChRs) containing the very closely related α6 and α3 subunits. nAChRs containing α3, α4, or α6 subunits in combination with β2, occasionally β4, and sometimes β3 or α5 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 snailConus purpurascens. The predicted peptide, α-conotoxin PIA, potently blocks the chimeric α6/α3β2β3 subunit combination as expressed in oocytes but neither the muscle nor the major neuronal nAChR α4β2. Additionally, this toxin is the first described ligand to discriminate between nAChRs containing α6 and α3 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.