The nicotinic ACh receptors (nAChRs) are members of a superfamily of ligand-gated ion channels. The receptors exist at the skeletal neuromuscular junction, autonomic ganglia, adrenal medulla and in the CNS. They are the natural targets for ACh as well as pharmacologically administered drugs, including nicotine. The receptor forms a pentameric structure consisting of homomeric a and b subunits. In humans, 8 a subunits (a2 through a7, a9, and a10) and three b subunits (b2 through b4) have been cloned. Both the muscle and neuronal nAChRs share structural and functional properties with other ligand-gated channels such as the GABAa, 5-HT3, and glycine receptors. The muscle nAChR is the best-characterized form. The muscle nicotinic receptor contains four distinct subunits in a pentameric complex (aJ38y or a2J38e; see Table 6-2). The muscle and neuronal subunits share the basic topography of a large extracellular N-terminal domain that contributes to agonist binding, four hydrophobic transmembrane domains (TM1 through TM4), a large cytoplasmic loop between TM3 and TM4, and a short extracellular C terminus. The M2 transmembrane region is thought to form the ion pore of the nAChR (see Chapter 9). Autonomic ganglia form homomeric a7 and het-eromeric a3/b4, with (a3)2(b4)3 being the most prevalent.
The pentameric structure of the neuronal nAChR and the considerable molecular diversity of its subunits offer the possibility of a large number of nAChRs with different physiological properties. These receptors may subserve a variety of discrete functions and thus represent novel drug targets for a wide variety of therapeutic agents. The stoichiometry of most nAChRs in brain is still uncertain. Distinctions amongst nAChRs are listed in Table 6—2. The structure, function, distribution, and subtypes of nicotinic receptors are described in more detail in Chapter 9.
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