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Species selectivity of a nicotinic acetylcholine receptor agonist is conferred by two adjacent extracellular beta 4 amino acids that are implicated in the coupling of binding to channel gating

Young, GT; Broad, LM; Zwart, R; Astles, PC; Bodkin, M; Sher, E; Millar, NS; (2007) Species selectivity of a nicotinic acetylcholine receptor agonist is conferred by two adjacent extracellular beta 4 amino acids that are implicated in the coupling of binding to channel gating. MOL PHARMACOL , 71 (2) 389 - 397. 10.1124/ml.106.030809.

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Abstract

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 beta 4-containing receptors. TMAQ also exhibits remarkable species selectivity, being a potent agonist of nAChRs containing the human beta 4 subunit but having no detectable agonist activity on nAChRs containing the rat beta 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 beta 4 subunits has been constructed. Recombinant receptors containing wild-type, chimeric, or mutated beta 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 beta 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 beta 4 subunit to the corresponding amino acids in the human beta 4 subunit (S55N and I56V mutations) confers sensitivity to TMAQ. The converse mutations in the human beta 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 beta 4-containing nAChRs, TMAQ acts as an antagonist of rat beta 4-containing receptors. Our experimental data, together with homology models of the rat and human alpha 3 beta 4 nAChRs, suggest that amino acids 55 and 56 may be involved in the coupling of agonist binding and channel gating.

Type: Article
Title: Species selectivity of a nicotinic acetylcholine receptor agonist is conferred by two adjacent extracellular beta 4 amino acids that are implicated in the coupling of binding to channel gating
DOI: 10.1124/ml.106.030809
Keywords: N-TERMINAL DOMAIN, SUBUNIT CHIMERAS, EXPRESSION, DIVERSITY, RESIDUES, ALPHA-7, CONTRIBUTE, IDENTIFICATION, DETERMINANTS, SENSITIVITY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1317284
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