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4
2 Neuronal Nicotinic
Acetylcholine Receptors by Cholinergic Channel Ligands and Second
Messenger Pathways
Neuroscience Research, Pharmaceutical Products Division, Abbott
Laboratories, Abbott Park, Illinois 60064-3500
The 
4
2 nicotinic acetylcholine receptors (nAChRs), a major
subtype in the brain, have been shown to be modulated by chronic treatment with nicotine. In this study, the regulation of recombinant human 42 nAChR subtype by (
)-nicotine and other cholinergic channel modulators was studied using human embryonic kidney 293 cells
stably expressing this subunit combination. The treatment of
transfected cells with ()-nicotine and other activator ligands, including ()-cytisine, 1,1-dimethyl-4-phenylpiperazinium,
(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and
(±)-epibatidine, resulted in concentration-dependent increases in the
levels of 42 nAChRs. The increase in [3H]cytisine
binding sites was initiated by low concentrations of ()-nicotine
(<100 nM); was maximal at 10 µM (15-fold),
rapid (t0.5 = 4.0 ± 0.5 hr), and totally
reversible (t0.5 = 11.7 ± 0.1 hr); and
occurred with no change in ligand binding affinity. Antagonists, including dihydro--erythroidine, d-tubocurarine, and
methyllycaconitine, also elicited significant increases in receptor
levels. A good correlation was observed between the
Ki values for binding inhibition and
the EC50 values for receptor up-regulation. Treatment of
cells with mecamy-lamine, a noncompetitive antagonist, did not change receptor levels or alter ()-nicotine-evoked up-regulation.
()-Nicotine-evoked up-regulation was blocked by cycloheximide,
suggesting a role for protein synthesis. Treatment of cells with
()-nicotine or dihydro--erythroidine differentially modulated the
efficacy of acetylcholine to activate cation efflux. Both
6--[
(piperidino)propionyl]forskolin and
phorbol-12-myristate-13-acetate increased [3H]cytisine
binding sites and nAChR function and enhanced the effects of chronic
()-nicotine treatment in a synergistic manner. These results
collectively demonstrate that human 42 nAChRs can be differentially up-regulated by chronic treatment with nAChR ligands and
activation of protein kinase A- and protein kinase C-dependent mechanisms.
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