Nicotine as a Nicotinic Acetylcholine Receptor Agonist
The initial molecular site of action for the physiological effects of nicotine is the nicotinic acetylcholine receptor (nAChR). nAChRs are cationic ligand-gated ion channels that are expressed throughout the central nervous system. Neuronal nAChRs can be presynaptic or postsynaptic and activate other neurons by increasing the influx of calcium, so producing neurotransmitter release. The influx of calcium on postsynaptic neurons can also trigger many cellular signal transduction processes, including the activation of protein kinase and calmodulin-dependent kinase. nAChRs are pentameric structures with at least two ligand-binding sites at the interface between subunits (Figure 7.13). A wide variety of nAChR subtypes with different pharmacological and electrophysiological properties exists. The genes that encode nAChR subunits have been identified and cloned in mammals (α1-α10 and β1-β9), and several subunits have been found in the central nervous system (α2-α7 and β2-β4). These subunits co-assemble to form functional pentameric receptors. Three distinct families of nAChRs are represented in the body and brain. The α1, β1, γ, δ, and ε subunits represent the muscle acetylcholine receptor family. The α2–6 and β2–4 subunits represent one central nervous system family. A third family can form homopentameric acetylcholine receptors composed of α7–10 subunits. All high-affinity binding sites for nicotine include the β2 subunit, a critical subunit for the reinforcing effects of nicotine.