Molecular Basis for the nicotine-induce upregulation of a4ß2 neuronal receptors.


Nicotine is the drug in tobacco that causes addiction. Chronic nicotine exposure in tobacco smokers and experimental animals produces an increase in brain binding sites for nicotine. Specifically, chronic nicotine administration induces the upregulation of mammalian α4β2 neuronal nicotinic acetylcholine receptor (nAChR) in the central nervous system (CNS). This upregulation of the α4β2 nAChR has been associated with nicotine tolerance and dependence. Furthermore, chronic nicotine exposure produces a long-lasting inactivation of the α4β2 nAChR subunit combination. Despite many years of study, the relationship between nicotine-induced effects on internal and cell surface number of nAChR and on nAChR function still remain unclear, due in part to a paucity in studies using the same model system to systematically measure nAChR number and function. In order to define the mechanism by which chronic nicotine exposure leads to an increase in the number of α4β2 nAChRs, it is necessary to understand how a conformational change in the receptor leads to upregulation and loss in function of this nAChR subtype. Our goal is to define the structural and functional basis for the upregulation of the α4β2 nAChR induced by chronic nicotine exposure.