Tacrine interacts with an allosteric activator site on alpha 4 beta 2 nAChRs in M10 cells

The effect of chronic treatment with the cholinesterase inhibitor tacrine on alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) was investigated in a transfected fibroblast cell line, M10. Tacrine significantly increased (+46%; 5 x 10(-8) to 10(-5) M) and decreased (-74%; 2 x 10(-5) to 10(-4) M) the number of nAChRs in the M10 cells in a concentration-dependent manner when using [3H]cytisine as labelled ligand. The mRNA levels for alpha 4 or beta 2 nAChR subunits remained unchanged following the treatment. The tacrine-induced increase in number of nAChRs was significantly blocked by the antagonist mecamylamine (10(-4) M), while tubocurarine (10(-4) M) had no effect. Neither of the antagonists prevented the decrease in the number of nAChRs obtained at the higher concentration of tacrine. Similar to nicotine, tacrine (5 x 10(-5) M) decreased the turnover rate of nAChRs, which might indicate neuroprotective properties. This study demonstrates that tacrine interacts with two sites on nAChRs, where activation of the noncompetitive allosteric site might contribute to the clinical efficacy of tacrine treatment in AD patients.