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Species Selectivity of a Nicotinic Acetylcholine Receptor Agonist Is Conferred by Two Adjacent Extracellular 4 Amino Acids that Are Implicated in the Coupling of Binding to Channel Gating

Department of Pharmacology, University College London, Gower Street, London, United Kingdom (G.T.Y., N.S.M.); and Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (L.M.B., R.Z., P.C.A., M.B., E.S.)

5-(Trifluoromethyl)-6-(1-methyl-azepan-4-yl)methyl-1H-quinolin-2-one (TMAQ) is a novel nicotinic acetylcholine receptor (nAChR) agonist with strong selectivity for 4-containing receptors. TMAQ also exhibits remarkable species selectivity, being a potent agonist of nAChRs containing the human 4 subunit but having no detectable agonist activity on nAChRs containing the rat 4 subunit. With the aim of identifying subunit domains and individual amino acids, which contribute to the species selectivity of TMAQ, a series of chimeric and mutated 4 subunits has been constructed. Recombinant receptors containing wild-type, chimeric, or mutated 4 subunits have been examined by radioligand binding, intracellular calcium assays, and electrophysiological recording. Two adjacent amino acids located within the extracellular loop D domain of the 4 subunit (amino acids 55 and 56) have been identified as playing a critical role in determining the agonist potency of TMAQ. Mutagenesis of these two residues within the rat 4 subunit to the corresponding amino acids in the human 4 subunit (S55N and I56V mutations) confers sensitivity to TMAQ. The converse mutations in the human 4 subunit (N55S and V56I) largely abolish sensitivity to TMAQ. In contrast, these mutations have little or no effect on sensitivity to the nonselective nicotinic agonist epibatidine. Despite acting as a potent agonist of human 4-containing nAChRs, TMAQ acts as an antagonist of rat 4-containing receptors. Our experimental data, together with homology models of the rat and human 34 nAChRs, suggest that amino acids 55 and 56 may be involved in the coupling of agonist binding and channel gating.

Address correspondence to: Dr. Neil S. Millar, Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. E-mail: n.millar{at}ucl.ac.uk

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