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42 Nicotinic Receptors with High and Low Acetylcholine Sensitivity: Pharmacology, Stoichiometry, and Sensitivity to Long-Term Exposure to Nicotine

School of Biological and Molecular Sciences, Oxford Brookes University, Oxford, United Kingdom (M.M., I.B.); Eli Lilly and Company Ltd., Lilly Research Centre, Windlesham, United Kingdom (R.Z., E.S.); and Department of Chemistry, University of Chile, Santiago, Chile (B.K.C.)

4 and 2 nicotinic acetylcholine receptor (nAChR) subunits expressed heterologously assemble into receptors with high (HS) and low (LS) sensitivity to acetylcholine (ACh); their relative proportions depend on the 4to 2 ratio. In this study, injection of oocytes with 1:10 4/2 subunit cDNA ratios favored expression of HS 42 nAChRs, as evidenced by monophasic ACh concentration-response curves, whereas injections with 10:1 cDNA ratios favored expression of LS 42 receptors. The stoichiometry was inferred from the shifts in the ACh EC₅₀ values caused by Leu to Thr mutations at position 9' of the second transmembrane domain of 4 and 2. The 1:10 injection ratio produced the (4)₂(2)₃ stoichiometry, whereas 10:1 injections produced the (4)₃(2)₂ stoichiometry. The agonists epibatidine, 3-[2(S)-azetidinylmethoxy]pyridine (A-85380), 5-ethoxy-metanicotine (TC-2559), cytisine, and 3-Br-cytisine and the antagonists dihydro--erythroidine and d-tubocurarine were more potent at HS receptors. TC-2559 was more efficacious than ACh at HS receptors but was a partial agonist at LS receptors. Epibatidine was more efficacious than ACh at LS receptors and a partial agonist at HS receptors. Cytisine and 5-halogenated cytisines had moderate efficacy at LS receptors but had almost no efficacy at HS receptors. By exploiting the differential effects of ACh, TC-2559 and 5-I-cytisine we evaluated the effects of long-term exposure to nicotine on HS and LS receptors expressed in Xenopus laevis oocytes after cDNA injections or microtransplantation of 42 receptors assembled in human embryonic kidney 293 cells. We conclude that nicotine up-regulates HS 42 receptors, probably by influencing the assembly of receptors rather than by altering the functional state of LS 42 nAChRs.

Address correspondence to: Isabel Bermudez, School of Biological and Molecular Sciences, Oxford Brookes University, Oxford OX3 0BP UK. E-mail: ibermudez{at}brookes.ac.uk

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