Muscarinic Receptors

General overview and M1 cholinergic receptors

Muscarinic cholinergic receptors are predominantly located on the postsynaptic membrane of effector organs that receive innervation from postganglionic parasympathetic fiber terminals. There are several major subtypes that differ in their localization and elicited effects.

M1 cholinergic receptors are diffusely represented in cholinergic synapses of the central nervous system (cortex, brainstem, midbrain, and spinal cord), where they are responsible for neuronal transmission.

Their most important peripheral function is the regulation of gastric secretion. In the stomach, they are located on enterochromaffin-like cells (ECL cells). The receptors are coupled with Gq proteins, and their stimulation increases the level of cytoplasmic calcium (Ca²⁺). This triggers a cascade: ECL cells release histamine, which secondary stimulates gastric parietal cells, causing them to actively secrete hydrochloric acid (HCl).

M2 cholinergic receptors: regulation of cardiac activity

These receptors are traditionally referred to as "cardiac" receptors. Their primary function is the inhibition of cardiac activity through specific ionic mechanisms. Stimulation of M2 receptors activates potassium channels, leading to an increased efflux of K⁺ ions and membrane hyperpolarization. Simultaneously, the phosphorylation of calcium channels decreases, which reduces the influx of Ca²⁺ ions into cardiomyocytes during depolarization.

Effects on cardiac regions:

• Sinoatrial (SA) node: spontaneous diastolic depolarization slows down, automatism decreases, and, consequently, heart rate drops (negative chronotropic effect).
• Atria: contractility decreases (negative inotropic effect), the refractory period is shortened, and impulse conduction through the atria is accelerated.
• Atrioventricular (AV) node: conduction velocity slows down and the refractory period is prolonged (negative dromotropic effect).
• Ventricles: contractility drops insignificantly because parasympathetic innervation in this area is poorly developed.

In addition to the heart, M2 receptors have a presynaptic localization on the membranes of postganglionic parasympathetic fiber terminals. Their excitation triggers a negative feedback mechanism: the release of the neurotransmitter (acetylcholine) into the synaptic cleft is inhibited.

M3 cholinergic receptors: smooth muscle, glands, and blood vessels

Innervated M3 receptors represent the largest group, mediating classical parasympathetic effects. Their molecular mechanism of action is also associated with Gq proteins: activation of phospholipase C leads to the generation of inositol 1,4,5-trisphosphate, the release of Ca²⁺ ions from the sarcoplasmic reticulum, and an increase in their cytoplasmic concentration.

Main targets of M3 receptors:

1. Eye: contraction of the circular muscle of the iris occurs (leading to pupil constriction — miosis) along with the ciliary muscle (causing spasm of accommodation, tuning the eye for near vision).
2. Smooth muscle of internal organs: tone increases (except for sphincters), and the motility of the bronchi, stomach, intestines, biliary tract, uterus, and urinary bladder is enhanced.
3. Exocrine glands: a generalized increase in secretion is observed (salivary, lacrimal, bronchial, gastric, sweat, nasopharyngeal, and intestinal glands).

A special subtype is non-innervated M3 muscarinic receptors. They have no synaptic connection with nerve endings, are localized on blood vessel endothelial cells, and respond to agonists circulating in the bloodstream. Stimulation of these receptors leads to the synthesis and release of endothelium-derived relaxing factor (NO — nitric oxide). NO penetrates the smooth muscle cells of the vascular wall, causing them to relax. As a result, vasodilation occurs and blood pressure decreases.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanism of phospholipase C activation and the role of inositol 1,4,5-trisphosphate during M3 receptor stimulation.
• Ionic basis of cardiomyocyte hyperpolarization (the role of potassium and calcium channels).
• Presynaptic regulation: the detailed negative feedback mechanism.
• Biochemistry of endothelium-derived relaxing factor (NO) synthesis and its effect on the vascular wall.

Other topics in the section «Drugs acting on cholinergic synapses»

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