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-Conotoxin MII Are Selective for 6-Containing Nicotinic Acetylcholine Receptors
Departments of Psychiatry (J.M.M.) and Biology (J.M.M., L.A., S.S., C.D.), University of Utah, Salt Lake City, Utah; University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.M.L., A.K.); Cognetix, Inc., Salt Lake City, Utah (J.E.G.); and Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (M.J.M., P.W.)
Neuronal nicotinic acetylcholine receptors (nAChRs) both mediate direct cholinergic synaptic transmission and modulate synaptic transmission by other neurotransmitters. Novel ligands are needed as probes to discriminate among structurally related nAChR subtypes. 
-Conotoxin MII, a selective ligand that discriminates among a variety of nAChR subtypes, fails to discriminate well between some subtypes containing the closely related 3 and 6 subunits. Structure-function analysis of -conotoxin MII was performed in an attempt to generate analogs with preference for 6-containing [6* (asterisks indicate the possible presence of additional subunits)] nAChRs. Alanine substitution resulted in several analogs with decreased activity at 3* versus 6* nAChRs heterologously expressed in Xenopus laevis oocytes. From the initial analogs, a series of mutations with two alanine substitutions was synthesized. Substitution at His9 and Leu15 (MII[H9A;L15A]) resulted in a 29-fold lower IC50 at 6
4 versus 34 nAChRs. The peptide had a 590-fold lower IC50 for 6/32 versus 32 and a 2020-fold lower IC50 for 6/323 versus 32 nAChRs. MII[H9A;L15A] had little or no activity at 22, 24, 34, 42, 44, and 7 nAChRs. Functional block by MII[H9A;L15A] of rat 6/323 nAChRs (IC50 = 2.4 nM) correlated well with the inhibition constant of MII[H9A;L15A] for [125I]-conotoxin MII binding to putative 62* nAChRs in mouse brain homogenates (Ki = 3.3 nM). Thus, structure-function analysis of -conotoxin MII enabled the creation of novel selective antagonists for discriminating among nAChRs containing 3 and 6 subunits.
Address correspondence to: Dr. J. Michael McIntosh, University of Utah, Department of Biology, 257 South 1400 East, Salt Lake City, UT 84112. E-mail: mcintosh{at}biology.utah.edu
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