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ACh: acetylcholine

AChE: acetylcholinesterase

AV: atrioventricular

eNOS: endothelial NO synthase

GI: gastrointestinal

GIRK channel: G protein-coupled inwardly-rectifying K+ channel

GRP: gastrin-releasing peptide

HCN: hyperpolarization-activated, cyclic nucleotide–gated channels

5HT: serotonin

ICa-L: L-type Ca2+ current

If: cardiac pacemaker current

IK-ACh: ACh-activated K+ current

IP3: inositol 1,4,5-trisphosphate

NAM: negative allosteric modulator

NO: nitric oxide

PAM: positive allosteric modulator

PIP2: phosphatidylinositol 4,5-bisphosphate

PLC: phospholipase C

SA: sinoatrial

TM: transmembrane


Muscarinic acetylcholine (ACh) receptors in the peripheral nervous system are found primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves. The actions of ACh and related drugs at autonomic effector sites are referred to as muscarinic, based on the observation that the alkaloid muscarine acts selectively at those sites and produces the same qualitative effects as ACh. The muscarinic, or parasympathomimetic, actions of the drugs considered in this chapter are practically equivalent to the parasympathetic effects of ACh listed in Table 10–1.

Muscarinic receptors are also present in autonomic ganglia and on some cells (e.g., vascular endothelial cells) that, paradoxically, receive little or no cholinergic innervation. Muscarinic receptors in autonomic ganglia and the adrenal medulla primarily function to modulate the nicotinic actions of ACh at these sites (Chapter 13). In the CNS, muscarinic receptors are widely distributed and have a role in mediating many important responses. Within the CNS, the hippocampus, cortex, and striatum have particularly high densities of muscarinic receptors.

ACh, the naturally occurring neurotransmitter for these receptors, has virtually no systemic therapeutic applications because its actions are diffuse, and its hydrolysis, catalyzed by both acetylcholinesterase (AChE) and plasma butyrylcholinesterase, is rapid. In addition, its penetration to the CNS is limited, and the amount of ACh that reaches peripheral areas with low blood flow is negligible due to its hydrolysis.

Muscarinic agonists mimic the muscarinic receptor–mediated effects of ACh. These agonists typically are longer-acting congeners of ACh or natural alkaloids, some of which stimulate nicotinic as well as muscarinic receptors. The differences between the actions of ACh and other muscarinic agonists at muscarinic receptors are largely quantitative, with limited selectivity for one organ system over another. All of the muscarinic actions of ACh and its congeners can be competitively inhibited by atropine.

Properties and Subtypes of Muscarinic Receptors

Muscarinic receptors were characterized initially by analysis of the responses of cells and organ systems in the periphery and the CNS. Differential effects of two muscarinic agonists, bethanechol and McN-A-343, on the tone of the lower esophageal sphincter led to the initial designation of muscarinic receptors as M1 (ganglionic) and M2 (effector cell) (Goyal and Rattan, 1978). This concept was supplanted by information obtained through molecular cloning of muscarinic receptors, which identified ...

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