Wikipedia

Muscarinic acetylcholine receptor

Muscarinic acetylcholine receptors(mAChRs) areacetylcholine receptorsthat formG protein-coupled receptor complexesin thecell membranesof certainneurons[1]and othercells.They play several roles, including acting as the main end-receptor stimulated byacetylcholinereleased frompostganglionic fibers.They are mainly found in theparasympathetic nervous system,but also have a role in thesympathetic nervous systemin the control ofsweat glands.[2]

Acetylcholine- the natural agonist of muscarinic andnicotinicreceptors.
Muscarine- an agonist used to distinguish between these two classes of receptors. Not normally found in the body.
Atropine- an antagonist.

Muscarinic receptors are so named because they are more sensitive tomuscarinethan tonicotine.[3]Their counterparts arenicotinic acetylcholine receptors(nAChRs), receptor ion channels that are also important in theautonomic nervous system.Many drugs and other substances (for examplepilocarpineandscopolamine) manipulate these two distinct receptors by acting as selectiveagonistsorantagonists.[4]

Function

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Acetylcholine (ACh)is aneurotransmitterfound in thebrain,neuromuscular junctionsand theautonomic ganglia. Muscarinic receptors are used in the following roles:

Recovery receptors

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The structure of Muscarinic acetylcholine receptor M2.

AChis always used as theneurotransmitterwithin 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 bymuscarinicreceptors, types M2and M1respectively (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 medullais 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 cellsof 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.

Postganglionic neurons

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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, andmuscarinicreceptors form the principal receptors on the innervated tissue.

Innervated tissue

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Very few parts of the sympathetic system use cholinergic receptors. In sweat glands the receptors are of themuscarinictype. The sympathetic nervous system also has some preganglionic nerves terminating at thechromaffin cellsin theadrenal medulla,which secreteepinephrineandnorepinephrineinto 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 thenicotinictype.

Thesomatic nervous systemuses anicotinicreceptor to acetylcholine at the neuromuscular junction.

Higher central nervous system

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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 forpostsynapticreceptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects.

Presynaptic membrane of the neuromuscular junction

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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.

Form of muscarinic receptors

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Muscarinic acetylcholine receptors belong to a class ofmetabotropic receptorsthat useG proteinsas their signaling mechanism. In such receptors, the signaling molecule (theligand) binds to a monomericreceptorthat 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 channelmechanism for signaling. In this case, binding of the ligands with the receptor causes anion channelto open, permitting either one or more specific types of ions (e.g., K+,Na+,Ca2+) to diffuse into or out of the cell.

Receptor isoforms

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Classification

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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,M5receptors are coupled withGqproteins,whileM2andM4receptors are coupled with Gi/oproteins.[5]There are other classification systems. For example, the drugpirenzepineis a muscarinic antagonist (decreases the effect of ACh), which is much more potent at M1receptors than it is at other subtypes. The acceptance of the various subtypes proceeded in numerical order, therefore, earlier sources may recognize only M1and M2subtypes,[citation needed]while later studies recognize M3,M4,[1]and most recently M5subtypes.[citation needed]

Genetic differences

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Meanwhile,geneticistsandmolecular biologistshave 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 M1and M2receptor proteins. The others were found by searching for homology, usingbioinformatictechniques.

Difference in G proteins

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See also:G-proteins

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). Gsand some subtypes of Gi(Gαtand Gαg) are susceptible to CTX. Only Giis 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.

Comparison of types
Type Gene Function PTX CTX Effectors Agonists[9] Antagonists[9]
M1 CHRM1 no
(yes)		 no
(yes)		 Gq
(Gi)
(Gs):
SlowEPSP.
↓K+conductance[12][16]
M2 CHRM2 yes no Gi
↑K+conductance[12]
↓Ca2+conductance[12]


M3 CHRM3 no no Gq
M4 CHRM4 yes ? Gi
↑K+conductance[12]
↓Ca2+conductance[12]


M5 CHRM5 no ? Gq

The muscarinic acetylcholine receptor subtypesectivitiesof a large number of antimuscarinic drugs have been reviewed.[24]

M1receptor

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Main article:Muscarinic acetylcholine receptor M1

This receptor is found mediating slowEPSPat the ganglion in the postganglionic nerve,[25]is common inexocrine glandsand in the CNS.[26][27]

It is predominantly found bound to G proteins of classGq,[28]which use upregulation ofphospholipaseC and, therefore,inositol trisphosphateand 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.

M2receptor

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Main article:Muscarinic acetylcholine receptor M2

The M2muscarinic receptors are located in the heart and lungs. In the heart, they act to slow theheart ratedown below the normal baselinesinus rhythm,by slowing the speed ofdepolarization.In humans, under resting conditions, vagal activity dominates over sympathetic activity. Hence, inhibition of M2receptors (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 theventricularmuscle.

M2muscarinic receptors act via aGitype 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.

M3receptor

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Main article:Muscarinic acetylcholine receptor M3

The M3muscarinic 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 M3receptor is Gq-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed duringbronchoconstrictionandbladder voiding.[29]However, with respect to vasculature, activation of M3on 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 ofparasympathomimeticson vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M3mediates vasoconstriction in diseases wherein the vascular endothelium is disrupted.[30] The M3receptors 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 M1muscarinic receptor, M3receptors are G proteins of classGqthat upregulatephospholipase Cand, therefore,inositol trisphosphateand intracellular calcium as a signaling pathway.[5]

M4receptor

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Main article:Muscarinic acetylcholine receptor M4

M4receptors are found in the CNS.

M4receptors work viaGireceptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. Possiblebronchospasmmay result if stimulated bymuscarinic agonists

M5receptor

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Main article:Muscarinic acetylcholine receptor M5

Location of M5receptors is not well known.

Like the M1and M3muscarinic receptor, M5receptors are coupled with G proteins of classGqthat upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.[citation needed]

Pharmacological application

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Ligandstargeting the mAChR that are currently approved for clinical use include non-selective antagonists for the treatment ofParkinson's disease,[31]atropine(to dilate thepupil),scopolamine(used to preventmotion sickness), andipratropium(used in the treatment ofCOPD).[4][32]

In 2024, theUnited States FDAapproved 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.[33]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 inPANSSvs 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.[33]

See also

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References

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