Nicotinic acetylcholine receptors (nAChRs) mediate the physiological effects of exogenous nicotine. They also play critical physiological roles throughout the brain and body by mediating cholinergic excitatory neurotransmission, modulating the release of neurotransmitters, and having longer-term effects on gene expression and cellular connections¹.

nAChRs are pentameric complexes made up of combinations of a number of different nAChR subunits. To date, 17 different but related subunits of nAChRs have been identified and cloned. They consist of α subunits (α1-10), which is responsible for the binding of ligands. In fact, this subunit includes a Cys-loop in the first extracellular domain that is required for agonist binding². The other subunits responsible for making up the active receptor are the β (β1-4), γ, δ and ε subunits³. Structurally, all subunits have the following: a conserved large extracellular N-terminal domain, three conserved transmembrane domains, a variable cytoplasmic loop and a fourth transmembrane domain with a short extracellular C-terminal domain. An active nAChR is generally a heteropentamer of these various subunits organized around a central pore¹. The β3 subunit cannot form functional receptors when expressed alone. It only forms operational channels when coexpressed with other functional subunit combinations, and is thus commonly termed ‘orphan’ or ‘auxiliary’ subunits³.

β3 nAChR subunit mRNA is highly expressed in dopaminergic neurons of the substantia nigra and ventral tegmental area⁴.

α6/β3 nAChRs have been implicated in dopaminergic neurotransmission, nicotine dependence, anxiety, and other important neurophysiological processes⁵.