Muscarinic Receptors And Muscarinic Agonists

Actions of acetylcholine (ACh) are referred to as muscarinic based on the observation that muscarine acts selectively at certain sites and, qualitatively, produces the same effects as ACh. Peripheral muscarinic acetylcholine receptors are found primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves and on some cells that receive little or no cholinergic innervation but express muscarinic receptors (e.g., vascular endothelial cells). There are also muscarinic receptors in ganglia and the adrenal medulla, where muscarinic stimulation seems to modulate the effects of nicotinic stimulation. Within the central nervous system (CNS), the hippocampus, cortex, and thalamus have high densities of muscarinic receptors.

Muscarinic agonists mimic the muscarinic effects of ACh and typically are longer-acting congeners of ACh or natural alkaloids that display little selectivity for the various subtypes of muscarinic receptors. The muscarinic, or parasympathomimetic, actions of the drugs considered in this chapter are practically equivalent to the effects of postganglionic parasympathetic nerve impulses listed in Table 6-1. All of the actions of ACh and its congeners at muscarinic receptors can be blocked by atropine.

Subtypes of Muscarinic Receptors

The cloning of complementary DNAs (cDNAs) encoding muscarinic receptors has identified five distinct gene products, designated as M] through Ms (see Table 6-3). All of the muscarinic receptor subtypes are G protein-coupled receptors (GPCRs). Although selectivity is not absolute, stimulation of M] and M3 receptors generally activates the G-PLC-1P3 pathway and mobilizes intracellular Ca2+, resulting in a variety of Ca2+-mediated events, either directly or as a consequence of the phosphorylation of target proteins. 1n contrast, M2 and M4 muscarinic receptors couple to Gt to inhibitadenylyl cyclase and to and Ggto regulate specific ion channels (e.g., enhancement of K+ conductance in cardiac sinoatrial [SA] nodal cells) through fig subunits of the G proteins.

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