Subtypes Of Muscarinic Receptors

In mammals, five distinct subtypes of muscarinic ACh receptors (mAChRs) have been identified, each produced by a different gene. Like the different forms of nicotinic receptors, these variants have distinct anatomical locations in the periphery and CNS and differing chemical specificities. The mAChRs are GPCRs (see Table 6-3). Muscarinic AChRs are present in virtually all organs, tissues, and cell types, although certain subtypes often predominate at specific sites. For example, the M2 receptor is the predominant subtype in the heart, whereas the M3 receptor is the predominant subtype in the bladder. In the periphery, mAChRs mediate the classical muscarinic actions of ACh in organs and tissues innervated by parasympathetic nerves; mAChRs are also present at sites that lack parasympathetic innervation (e.g., on endothelial and smooth muscle cells of most blood vessels). In the CNS, mAChRs are involved in regulating a large number of cognitive, behavior, sensory, motor, and autonomic functions. The basic functions of muscarinic cholinergic receptors (Table 6—3) are mediated by interactions with G proteins and thus by G protein—induced changes in the function of distinct member-bound effector molecules. The M,, M3, and Ms subtypes couple through the pertussis toxin—insensitive G^ Gn, and G12/B to stimulate the PLC-IP3-Ca2+ pathway, with activation of Ca2+-dependent phenomena such as contraction of smooth muscle and secretion (see Chapter 1). Another product of PLC activation, diacylglycerol, in conjunction with Ca2+, activates PKC, resulting in the phosphorylation of numerous proteins and leading to various physiological responses. Activation of M, M3, and Ms receptors can also cause the activation of phospholipase A2, leading to the release of arachidonic acid and consequent eicosanoid synthesis, resulting in autocrine/paracrine stimulation of adenylyl cyclase.

Stimulation of M2 and M4 cholinergic receptors leads to interaction with other G proteins, (e.g., and G J with a resulting inhibition of adenylyl cyclase, a decrease in cyclic AMP, activation of inwardly rectifying K+ channels, and inhibition of voltage-gated Ca2+ channels, with the functional consequences of hyperpolarization and inhibition of excitability. These are most clear in myocardium, where inhibition of adenylyl cyclase and activation of K+ conductances account for the negative chronotropic and inotropic effects of ACh.

Table 6-2

Characteristics of Subtypes of Nicotinic Acetylcholine Receptors (nAChRs)

Receptor (Primary

Main Synaptic



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