Mechanisms of nicotine induced up-regulation of alfa 4 beta 2 AChRs

ABSTRACT

Nicotinic acetylcholine receptors (AChRs) formed from α4 and β2 subunits comprise the predominant brain AChR subtype with high affinity for nicotine. Human α4 β2 AChRs in a permanently transfected cell line were shown to be activated, desensitized, and upregulated by nicotine. Continuous exposure to nicotine increased the amount of AChRs by two mechanisms. Nicotine acted on assembly intermediates as a pharmacological chaperone to promote assembly of mature AChRs. Over the first few hours, this mechanism accounted for most upregulation. Nicotine also increased the lifetime of AChRs in the cell surface, thereby further contributing to upregulation. A cell line expressing mutant S247F α4β2 AChRs exhibited little nicotine¬induced AChR function but substantial nicotine-induced upregulation. This mutation is a cause of autosomal dominant nocturnal front lobe epilepsy (ADNFLE).