Acetylcholine receptors named for their selective binding of muscarine
Acetylcholine - the natural agonist of muscarinic andnicotinic receptors.Muscarine - an agonist used to distinguish between these two classes of receptors. Not normally found in the body.Atropine - an antagonist.
The structure of Muscarinic acetylcholine receptor M2.
ACh is always used as theneurotransmitter within theautonomic ganglion. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization (FastEPSP) of that neuron. As a consequence of this, nicotinic receptors are often cited asthe 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 bymuscarinic receptors, types M2 and M1 respectively (discussed below).[citation needed]
Peripheral autonomic fibers (sympathetic and parasympathetic fibers) are categorized anatomically as either preganglionic orpostganglionic 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.
Theadrenal 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. Thechromaffin 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, andmuscarinic 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 themuscarinic type. The sympathetic nervous system also has some preganglionic nerves terminating at thechromaffin cells in theadrenal medulla, which secreteepinephrine andnorepinephrine into the bloodstream. Some[who?] believe that chromaffin cells are modified postganglionic CNS fibers. In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of thenicotinic type.
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 forpostsynaptic receptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects.
Presynaptic membrane of the neuromuscular junction
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 ofmetabotropic receptors that useG proteins as their signaling mechanism. In such receptors, the signaling molecule (theligand) binds to a monomericreceptor that hasseven 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.[5]
By contrast, nicotinic receptors form pentameric complexes and use aligand-gated ion channel mechanism for signaling. In this case, binding of the ligands with the receptor causes anion channel to open, permitting either one or more specific types of ions (e.g., K+, Na+, Ca2+) to diffuse into or out of the cell.
By the use of selective radioactively labeled agonist and antagonist substances, five subtypes of muscarinic receptors have been determined, named M1–M5 (using an upper case M and subscript number).[6]M1,M3,M5 receptors are coupled withGq proteins, whileM2 andM4 receptors are coupled with Gi/o proteins.[5] There are other classification systems. For example, the drugpirenzepine 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,[citation needed] while later studies recognize M3, M4,[1] and most recently M5 subtypes.[citation needed]
Meanwhile,geneticists andmolecular 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, usingbioinformatic techniques.
G proteins contain an alpha-subunit that is critical to the functioning of receptors. These subunits can take a number of forms. There are four broad classes of form of G-protein: Gs, Gi, Gq, and G12/13.[7] Muscarinic receptors vary in the G protein to which they are bound, with some correlation according to receptor type. G proteins are also classified according to their susceptibility tocholera toxin (CTX) andpertussis toxin (PTX, whooping cough). Gs and some subtypes of Gi (Gαt and Gαg) are susceptible to CTX. Only Gi is susceptible to PTX, with the exception of one subtype of Gi (Gαz) which is immune. Also, only when bound with an agonist, those G proteins normally sensitive to PTX also become susceptible to CTX.[8]
The various G-protein subunits act differently upon secondary messengers, upregulating Phospholipases, downregulating cAMP, and so on.
Because of the strong correlations to muscarinic receptor type, CTX and PTX are useful experimental tools in investigating these receptors.
This receptor is found mediating slowEPSP at the ganglion in the postganglionic nerve,[29] is common inexocrine glands and in the CNS.[30][31]
It is predominantly found bound to G proteins of classGq,[32] which use upregulation ofphospholipase C and, therefore,inositol trisphosphate and intracellular calcium as a signaling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, Gi (causing a downstream decrease incAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX, respectively.
The M2 muscarinic receptors are located in the heart and lungs. In the heart, they act to slow theheart rate down below the normal baselinesinus rhythm, by slowing the speed ofdepolarization. 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 theatrialcardiac muscle, and reduce conduction velocity of theatrioventricular node (AV node). It also serves to slightly decrease the contractile forces of theventricular muscle.
M2 muscarinic receptors act via aGi 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 duringbronchoconstriction andbladder voiding.[33] However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis ofnitric oxide,which diffuses to adjacent vascular smooth muscle cells and causes their relaxation, thereby explaining the paradoxical effect ofparasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M3 mediates vasoconstriction in diseases wherein the vascular endothelium is disrupted.[34]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 classGq that upregulatephospholipase C and, therefore,inositol trisphosphate and intracellular calcium as a signaling pathway.[5]
M4 receptors are found in the CNS. M4 receptors are also located in erythroidprogenitor cell in peripheral tissue and modulate the cAMP pathway to regulate erythroid progenitor cell differentiation. Therapies targeting the M4 receptor treatsmyelodysplastic syndrome andanemia that are refractory toerythropoietin.[24][25][26][27]
M4 receptors work viaGi receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. Possiblebronchospasm may result if stimulated bymuscarinic agonists.
Like the M1 and M3 muscarinic receptor, M5 receptors are coupled with G proteins of classGq that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.[citation needed]
In 2024, theUnited States FDA approved the drugKarXT (Cobenfy), which is a combination drug that combinesxanomeline (a preferentially acting M1/M4 muscarinic acetylcholine receptor agonist) withtrospium (a peripherally-restricted pan-mAChR antagonist for use in schizophrenia.)[37] In early clinical trials of moderate to high severity patients without treatment resistant history, it has demonstrated efficacy about equivalent to that of other anti-psychotics (20-point improvement inPANSS vs 10-point placebo improvement), with a notably different side effect profile (very low rates of metabolic effects, hypotension, weight changes, or EPS) with moderately reported rates of nausea and constipation. No trials have been published to date regarding use in combination with other antipsychotics, use in treatment resistant patients, or head-to-head comparisons with other medications. This is the first anti-psychotic drug approved that uses a muscarinic mechanism of action, and many others are in development.[37]
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^Moro C, Uchiyama J, Chess-Williams R (December 2011). "Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol".Urology.78 (6): 1442.e9–15.doi:10.1016/j.urology.2011.08.039.PMID22001099.
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