Мускариновые ацетилхолиновые рецепторы: структура и функции.

Acetylcholine receptors named for their selective binding of muscarine

Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system. Muscarinic receptors are so named because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.

ACh is always used as the neurotransmitter within the autonomic ganglion. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization (Fast EPSP) of that neuron. As a consequence of this, nicotinic receptors are often cited as the receptor on the postganglionic neurons at the ganglion. However, the subsequent hyperpolarization (IPSP) and slow depolarization (Slow EPSP) that represent the recovery of the postganglionic neuron from stimulation are actually mediated by muscarinic receptors, types M2 and M1 respectively (discussed below). Peripheral autonomic fibers (sympathetic and parasympathetic fibers) are categorized anatomically as either preganglionic or postganglionic fibers, then further generalized as either adrenergic fibers, releasing noradrenaline, or cholinergic fibers, both releasing acetylcholine and expressing acetylcholine receptors. Both preganglionic sympathetic fibers and preganglionic parasympathetic fibers are cholinergic. Most postganglionic sympathetic fibers are adrenergic: their neurotransmitter is norepinephrine except postganglionic sympathetic fibers to the sweat glands, piloerectile muscles of the body hairs, and the skeletal muscle arterioles do not use adrenaline/noradrenaline. The adrenal medulla is considered a sympathetic ganglion and, like other sympathetic ganglia, is supplied by cholinergic preganglionic sympathetic fibers: acetylcholine is the neurotransmitter utilized at this synapse. The chromaffin cells of the adrenal medulla act as "modified neurons", releasing adrenaline and noradrenaline into the bloodstream as hormones instead of as neurotransmitters. The other postganglionic fibers of the peripheral autonomic system belong to the parasympathetic division; all are cholinergic fibers, and use acetylcholine as the neurotransmitter.

Another role for these receptors is at the junction of the innervated tissues and the postganglionic neurons in the parasympathetic division of the autonomic nervous system. Here acetylcholine is again used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue.

Very few parts of the sympathetic system use cholinergic receptors. In sweat glands the receptors are of the muscarinic type. The sympathetic nervous system also has some preganglionic nerves terminating at the chromaffin cells in the adrenal medulla, which secrete epinephrine and norepinephrine into the bloodstream. Some believe that chromaffin cells are modified postganglionic CNS fibers. In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type. The somatic nervous system uses a nicotinic receptor to acetylcholine at the neuromuscular junction.

Muscarinic acetylcholine receptors are also present and distributed throughout the local nervous system, in post synaptic and pre synaptic positions. There is also some evidence for postsynaptic receptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects.

It is known that muscarinic acetylcholine receptors also appear on the pre synaptic membrane of somatic neurons in the neuro muscular junction, where they are involved in the regulation of acetylcholine release.

Muscarinic acetylcholine receptors belong to a class of metabotropic receptors that use G proteins as their signaling mechanism. In such receptors, the signaling molecule (the ligand) binds to a monomeric receptor that has seven transmembrane regions; in this case, the ligand is ACh. This receptor is bound to intracellular proteins, known as G proteins, which begin the information cascade within the cell. M1, M3, M5 receptors are coupled with Gq proteins, while M2 and M4 receptors are coupled with Gi/o proteins. There are other classification systems. For example, the drug pirenzepine is a muscarinic antagonist (decreases the effect of ACh), which is much more potent at M1 receptors than it is at other subtypes. The acceptance of the various subtypes proceeded in numerical order, therefore, earlier sources may recognize only M1 and M2 subtypes, while later studies recognize M3, M4, and most recently M5 subtypes.

Meanwhile, geneticists and molecular biologists have characterised five genes that appear to encode muscarinic receptors, named m1 m5 (lowercase m; no subscript number). They code for pharmacologic types M1 M5. The receptors m1 and m2 were determined based upon partial sequencing of M1 and M2 receptor proteins. The others were found by searching for homology, using bioinformatic techniques.

The M2 muscarinic receptors are located in the heart and lungs. In the heart, they act to slow the heart rate down below the normal baseline sinus rhythm, by slowing the speed of depolarization. In humans, under resting conditions, vagal activity dominates over sympathetic activity. Hence, inhibition of M2 receptors (e. g. by atropine) will cause a raise in heart rate. They also moderately reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). It also serves to slightly decrease the contractile forces of the ventricular muscle. M2 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, inhibition of voltage gated Ca2+ channels, and increasing efflux of K+, in general, leading to inhibitory type effects.

The M3 muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. Because the M3 receptor is Gq coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during bronchoconstriction and bladder voiding. However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M3 mediates vasoconstriction in diseases wherein the vascular endothelium is disrupted. The M3 receptors are also located in many glands, which help to stimulate secretion in, for example, the salivary glands, as well as other glands of the body. Like the M1 muscarinic receptor, M3 receptors are G proteins of class Gq that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway. atropine (to dilate the pupil), scopolamine (used to prevent motion sickness), and ipratropium (used in the treatment of COPD).