Tacrine interacts with an allosteric activator site on α4β2 nAChRs in M10 cells

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Abstract
The effect of chronic treatment with the cholinesterase inhibitor tacrine on α4β2 nicotinic acetylcholine receptors (nAChRs) was investigated in a transfected fibro-blast cell line, M10. Tacrine significantly increased (+46%; 5 ± 10−8 to 10−5 M) and decreased (-74%; 2 ± 10−5 to 10−4 M) the number of nAChRs in the M10 cells in a concentration-dependent manner when using [3H]cyti-sine as labelled ligand. The mRNA levels for α4 or β2 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 ± 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 non-competitive allosteric site might contribute to the clinical efficacy of tacrine treatment in AD patients.

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