MUSCARINIC RECEPTORS: STRUCTURE, TYPES AND THEIR FUNCTIONS, ANTAGONISTS - BIOLOGY - 2025

The muscarinic receptors are molecules that mediate the actions of acetylcholine (ACh) and are located in the postsynaptic membrane of synapses in which said neurotransmitter is released; its name comes from its sensitivity to the muscarine alkaloid produced by the Amanita muscaria fungus.

In the central nervous system there are several neuronal assemblages whose axons release acetylcholine. Some of them end up in the brain itself, while most make up the motor pathways for skeletal muscle or the effector pathways of the autonomic nervous system for the glands and cardiac and smooth muscles.

The neuroreceptor acetylcholine during synapse and its respective receptors in the postsynaptic membrane (Source: user: Pancrat via Wikimedia Commons)

Acetylcholine released at the neuromuscular junctions of skeletal muscle activates cholinergic receptors called nicotinic receptors, due to their sensitivity to the alkaloid nicotine, and which are also found in the ganglionic synapses of the autonomic nervous system (ANS).

The postganglionic neurons of the parasympathetic division of this system exert their functions by releasing acetylcholine, which acts on the muscarinic cholinergic receptors located on the effector cell membranes, and inducing electrical modifications in them due to permeability changes in their ion channels.

Chemical structure of the neurotransmitter acetylcholine (Source: NEUROtiker via Wikimedia Commons)

Structure

Muscarinic receptors belong to the family of metabotropic receptors, a term that designates those receptors that are not properly ion channels, but rather protein structures that, when activated, trigger intracellular metabolic processes that modify the activity of the true channels.

The term is used to differentiate them from ionotropic receptors, which are true ionic channels that open or close by the direct action of the neurotransmitter, as is the case of the nicotinic receptors already mentioned in the neuromuscular plates of skeletal muscle.

Within the metabotropic receptors, muscarinic receptors are included in the group known as G-protein coupled receptors, because depending on their type, their action is mediated by some variants of said protein, such as Gi, an inhibitor of adenyl cyclase, and Gq or G11 which activate phospholipase C (PLC).

Muscarinic receptors are long integral membrane proteins; They have seven transmembrane segments composed of alpha helices, which sequentially cross the membrane lipid bilayer. Inside, on the cytoplasmic side, they associate with the corresponding G protein that transduces the ligand-receptor interaction.

Types of muscarinic receptors and their functions

At least 5 types of muscarinic receptors have been identified and are designated using the letter M followed by a number, namely: M1, M2, M3, M4 and M5.

The M1, M3 and M5 receptors form the M1 family and are characterized by their association with Gq or G11 proteins, while the M2 and M4 receptors are from the M2 family and are associated with the Gi protein.

- M1 receivers

They are found mainly in the central nervous system, in the exocrine glands, and in the ganglia of the autonomic nervous system. They are coupled to protein Gq, which activates the enzyme phospholipase C, which converts phosphatidyl inositol (PIP2) to inositol triphosphate (IP3), which releases intracellular Ca ++, and diacylglycerol (DAG), which activates protein kinase C.

- M2 receivers

They are found mainly in the heart, mainly in the cells of the sinoatrial node, on which they act by decreasing their discharge frequency, as described below.

Heart automatism

M2 receptors have been studied in greater depth at the level of the sinoatrial (SA) node of the heart, a place where the automatism that periodically produces the rhythmic excitations responsible for cardiac mechanical activity is normally manifested.

The cells of the sinoatrial node, after each action potential (AP) that triggers a cardiac systole (contraction), repolarize and return to the level of about -70 mV. But the voltage does not remain at that value, but undergoes progressive depolarization to a threshold level that triggers a new action potential.

This progressive depolarization is due to spontaneous changes in ionic currents (I) that include: reduction of K + output (IK1), appearance of an input current of Na + (If) and then an input of Ca ++ (ICaT), until it reaches the threshold and another Ca ++ current (ICaL) is triggered, responsible for the action potential.

If the K + (IK1) output is very low and the Na + (If) and Ca ++ (ICaT) input currents are high, depolarization occurs faster, the action potential and contraction occur earlier, and the frequency heart rate is higher. Contrary modifications in those currents lower the frequency.

Metabotropic changes induced by norepinephrine (sympathetic) and acetylcholine (parasympathetic) can alter these currents. CAMP directly activates If channels, protein kinase A (PKA) phosphorylates and activates Ca ++ channels of ICaT, and the βγ group of Gi protein activates K + output.

Muscarinic action M2

When acetylcholine released by the postganglionic endings of cardiac vagal (parasympathetic) fibers binds to the M2 muscarinic receptors of the cells of the sinoatrial node, the αi subunit of the Gi protein exchanges its GDP for GTP and separates, freeing the block. βγ.

The αi subunit inhibits adenyl cyclase and reduces cAMP production, which reduces the activity of the If and PKA channels. This last fact reduces the phosphorylation and activity of the Ca ++ channels for ICaT; the result is a reduction in depolarizing currents.

The group formed by the βγ subunits of the Gi protein activates an outward K + current (IKACh) that tends to counteract the inputs of Na + and Ca ++ and lowers the rate of depolarization.

The overall result is a reduction in the spontaneous depolarization slope and a reduction in heart rate.

- M3 receivers

Muscarinic M3 receptor schematic (Source: Takuma-sa via Wikimedia Commons)

They can be found in smooth muscle (digestive system, bladder, blood vessels, bronchi), in some exocrine glands, and in the central nervous system.

They are also coupled to Gq protein and, at the pulmonary level, they can cause bronchoconstriction, while acting on the vascular endothelium they release nitric oxide (NO) and cause vasodilation.

- M4 and M5 receivers

These receptors are less characterized and studied than the previous ones. Its presence in the central nervous system and in some peripheral tissues has been reported, but its functions are not clearly established.

Antagonists

The universal antagonist for these receptors is atropine, an alkaloid extracted from the plant Atropa belladonna, which binds to them with a high affinity, which represents a criterion to differentiate them from nicotinic receptors that are insensitive to this molecule.

There are a large number of other antagonist substances that bind to different types of muscarinic receptors with different affinities. The combination of different affinity values ​​for some of them has served precisely for the inclusion of these receptors in one or another of the categories described.

A partial list of other antagonists would include: pirenzepine, methoctramine, 4-DAMP, himbazine, AF-DX 384, tripitramine, darifenacin, PD 102807, AQ RA 741, pFHHSiD, MT3 and MT7; toxins the latter contained in the poisons of the green and black mambas, respectively.

M1 receptors, for example, have a high sensitivity for pirenzepine; the M2s by tryptramine, methoctramine and himbazine; the M3s by 4-DAMP; the M4 are closely related to the MT3 toxin and also to himbacin; The M5s are very similar to the M3s, but with respect to them they are less related by AQ RA 741.

References

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