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Received for publication January 30, 2006.
Revised May 19, 2006.
Accepted for publication May 22, 2006.
4
2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry and sensitivity to chronic exposure to nicotine
4 and 
2 nicotinic acetylcholine receptor (nAChR) subunits expressed heterologously assemble into high (HS) and low (LS) ACh sensitivity receptors whose relative proportions depend on the 4 to 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, whilst injections with 10:1 cDNA ratios favored expression of LS 4[beta]2 receptors. The stoichiometry was inferred from the shifts in the ACh EC50 values caused by L to T 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, whilst 10:1 injections produced the (4)3(2)2 stoichiometry. The agonists epibatidine, A-85380, TC-2559, cytisine and 3-Br-cytisine and the antagonists dihydro--erythroidine (DHE) 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 chronic exposure to nicotine on HS and LS receptors expressed in Xenopus oocytes after cDNA injections or microtransplantation of 42 receptors assembled in HEK293 cells. We conclude that nicotine upregulates HS 42 receptors, likely by influencing the assembly of receptors, rather than by altering the functional state of LS 42 nAChRs.
Key words:
Nicotinic cholinergic, Ion channel regulation, Func. analysis receptor/ion channel mutants
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