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Pharmacological Properties of 910 Nicotinic Acetylcholine Receptors Revealed by Heterologous Expression of Subunit Chimeras

Department of Pharmacology, University College London, London, United Kingdom (E.R.B, N.S.M); and Eli Lilly and Company Limited, Lilly Research Centre, Windlesham, Surrey, United Kingdom (R.Z., E.S.)

The nicotinic acetylcholine receptor (nAChR) 9 and 10 subunits are expressed primarily within hair cells of the inner ear and have been implicated in auditory processing. Although functional recombinant nAChRs generated by the coexpression of 9 and 10 in Xenopus laevis oocytes have been described previously, there have been no reports of the successful heterologous expression of 910 nAChRs in cultured cell lines. In this study, subunit chimeras (9 and 10) have been constructed that contain the extracellular, ligand binding domain of the 9 or 10 subunits fused to the C-terminal domain of the 5-hydroxytryptamine type 3A (5HT_3A) subunit. Specific high-affinity binding of the nicotinic radioligand [³H]methyllycaconitine was detected in membrane preparations of mammalian cells transfected with 9 or 10 alone, but significantly higher levels of binding were detected when 9 and 10 were cotransfected, providing evidence of a requirement for coassembly of 9 and 10 for the efficient formation of a nicotinic binding site. The pharmacological profile of 910 receptors, determined by equilibrium radioligand binding studies, is broadly similar to that determined previously by electrophysiological studies conducted with native and recombinant 910 nAChRs. In agreement with evidence that 910 nAChRs exhibit an atypical pharmacological profile, we have identified specific high-affinity binding of several non-nicotinic ligands including strychnine (a glycine receptor antagonist), bicuculline (a GABA_A receptor antagonist), and atropine (a muscarinic acetylcholine receptor antagonist). Results have also been compared with radioligand binding data conducted with a previously described 7/5HT_3A (7) subunit chimera.

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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