4.1.1 Structure, Composition, and Distribution
Nicotinic acetylcholine receptors (nAChRs) belong to the ligand-gated ion channel receptor superfamily: nAChRs are composed of 5 subunits arranged to form an integral ion channel that can open upon binding the neurotransmitter, ACh, or exogenous ligands, such as nicotine. Muscle type nAChRs are found at the neuromuscular junction and in the electric organs of fish. The muscle nAChRs are very well-characterized and will be noted but not discussed in this chapter. More recently, neuronal type nAChRs were identified in neurons in the central and peripheral nervous systems and also in epithelia. The nAChR family is found throughout the central nervous system (CNS), in the peripheral autonomic nervous system, in adrenal chromaffin cells, and also in skin, the cornea, cochlear, and bronchial epithelial cells (Nguyen et al., 2000b). Their functions, which are just beginning to be elucidated, are a subject of intense investigation (Cordero-Erausquin et al., 2000; Wessler et al., 1999).
The naming of nAChRs (in the CNS and PNS) followed that of the muscle nAChR. Muscle nAChRs are composed of 5 subunits: 2 al, p1, y/e, and 5. In neurons, 8 further a subunits have been identified (a2-a9), and 3 further subunits that have been named p2, p3, and p4 (or, in some cases, non-a subunits) (Arias, 2000). Within the same species, a subunits in neurons show about 50% homology with a subunits in muscle. Both muscle and neuronal nAChR subunit genes encode peptides that have 4 hydrophobic domains that are putative transmembrane regions: here, the homology approaches 100%. Both a and p subunits appear to contribute to the physiological and pharmacological properties of nAChRs (Arias, 2000). Among the different subunits, only a7, a8, and a9 can form functional receptors alone; a2-a4 require p subunits to make functional receptors. Recent in vitro studies, however, have indicated that this classification may be too simplistic in that a7 subtypes may combine with other subunits, thus markedly increasing the possibilities of the functional nAChRs subtypes (Crabtree et al., 1997; Gotti et al., 1994). Studies have shown that a5 subunits will not form functional receptors in combination with P subunits alone, but can contribute to functional receptors with p subunits and other a subunits. Also p3 subunits may combine with a6 and p2 subunits to form functional channels (Cordero-Erausquin et al., 2000). In general, however, the precise combinations of subunits that comprise functional nAChRs in neurons, glia, or epithelial cells are not known.
In this chapter, we will review the current status of peripheral nAChRs in neurons and in epithelia. Although nAChRs are found in many epithelia, we will focus on their roles in skin since this has been the most extensively studied peripheral system and also because some of their functions have been elucidated (Grando, 1997; Grando and Horton, 1997). The emphasis of this chapter will be on how different methodological approaches have contributed to present understanding of peripheral nAChR structure and function.
Like the muscle AChR, neuronal AChRs are cation-selective ion channels that depolarize cells when they are gated open by endogenous ligands. Certain nAChR subtypes have a relatively high permeability to Ca2+ ions (see Figure 4.7), which can subsequently act as a signaling molecule (Seguela et al., 1993; Vernino et al., 1992). In the PNS, nAChRs are found at synapses, as well as extrasynaptically, where they can modulate transmitter release (Sargent and Garrett, 1995; Schechter and Rosecrans, 1971). In sensory neurons in the PNS they may signal the onset of pain and inflammation and in non-neuronal cells they serve many functions, including modulating cell adhesion (Grando and Horton, 1997).
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