Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons<ref name="pmid16879488">Template:Cite journal</ref> and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers. They are mainly found in the parasympathetic nervous system, but also have a role in the sympathetic nervous system in the control of sweat glands.<ref>Template:Citation</ref>
Muscarinic receptors are so named because they are more sensitive to muscarine than to nicotine.<ref name="pmid17073660">Template:Cite journal</ref> 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.<ref name="Purves" >Template:Cite book</ref>
FunctionEdit
Acetylcholine (ACh) is a neurotransmitter found in the brain, neuromuscular junctions and the autonomic ganglia. Muscarinic receptors are used in the following roles:
Recovery receptorsEdit
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).Template:Citation needed
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.
Postganglionic neuronsEdit
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.
Innervated tissueEdit
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. SomeTemplate: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 the nicotinic type.
The somatic nervous system uses a nicotinic receptor to acetylcholine at the neuromuscular junction.
Higher central nervous systemEdit
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.
Presynaptic membrane of the neuromuscular junctionEdit
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 receptorsEdit
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.<ref name="Kou Qin"/>
By contrast, nicotinic receptors form pentameric complexes and use a ligand-gated ion channel mechanism for signaling. In this case, binding of the ligands with the receptor causes an ion 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.
Receptor isoformsEdit
ClassificationEdit
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).<ref name="pmid9647869">Template:Cite journal</ref> M1, M3, M5 receptors are coupled with Gq proteins, while M2 and M4 receptors are coupled with Gi/o proteins.<ref name="Kou Qin">Template:Cite journal</ref> 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,Template:Citation needed while later studies recognize M3, M4,[1] and most recently M5 subtypes.Template:Citation needed
Genetic differencesEdit
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.
Difference in G proteinsEdit
Template:See also 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.<ref name="pmid1902986">Template:Cite journal</ref> 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 to cholera toxin (CTX) and pertussis 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.<ref name="pmid8449930">Template:Cite journal</ref>
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.
| Type | Gene | Function | PTX | CTX | Effectors | Agonists<ref name="Tripathi_2004">Template:Cite book if nothing else mentioned in table</ref> | Antagonists<ref name="Tripathi_2004" /> | |
|---|---|---|---|---|---|---|---|---|
| M1 | Template:Gene |
|
no (yes) |
no (yes) |
Gq (Gi) (Gs): Slow EPSP. ↓ K+ conductance<ref name=Rang/><ref name="pmid1693682">Template:Cite journal</ref> |
|
|
CitationClass=web
}} </ref>
Template:Cite journal</ref>
|
| M2 | Template:Gene |
|
yes | no | Gi ↑ K+ conductance<ref name=Rang/> ↓ Ca2+ conductance<ref name=Rang/> |
|
| |
| M3 | Template:Gene |
|
no | no | Gq |
|
| |
| M4 | Template:Gene |
|
yes | ? | Gi ↑ K+ conductance<ref name=Rang/> ↓ Ca2+ conductance<ref name=Rang/> |
|
| |
| M5 | CHRM5 |
|
no | ? | Gq |
|
|
The muscarinic acetylcholine receptor subtype sectivities of a large number of antimuscarinic drugs have been reviewed.<ref name="LavradorCabralVeríssimo2023">Template:Cite journal</ref>
M1 receptorEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve,<ref name="pmid27347892">Template:Cite journal</ref> is common in exocrine glands and in the CNS.<ref name="isbn1-55009-109-3">Template:Cite book</ref><ref name="Richelson_2000">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
It is predominantly found bound to G proteins of class Gq,<ref name="pmid8645172">Template:Cite journal</ref> which use upregulation of phospholipase 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 in cAMP) 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.
M2 receptorEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.
M3 receptorEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.<ref name="Moro et al. 2011">Template:Cite journal</ref> 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.<ref name="isbn0-07-142280-3">Template:Cite book</ref> 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.<ref name="Kou Qin"/>
M4 receptorEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} M4 receptors are found in the CNS. M4 receptors are also located in erythroid progenitor cell in peripheral tissue and modulate the cAMP pathway to regulate erythroid progenitor cell differentiation. Therapies targeting the M4 receptor treats myelodysplastic syndrome and anemia that are refractory to erythropoietin.<ref name=”pmid31554738”>Template:Cite journal</ref><ref name=”pmid35034954”>Template:Cite journal</ref><ref name=”pmid34257007”>Template:Cite journal</ref>
M4 receptors work via Gi receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. Possible bronchospasm may result if stimulated by muscarinic agonists.
M5 receptorEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Location of M5 receptors is not well known.
Like the M1 and M3 muscarinic receptor, M5 receptors are coupled with G proteins of class Gq that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.Template:Citation needed
Pharmacological applicationEdit
Ligands targeting the mAChR that are currently approved for clinical use include non-selective antagonists for the treatment of Parkinson's disease,<ref name="pmid18082893">Template:Cite journal</ref> atropine (to dilate the pupil), scopolamine (used to prevent motion sickness), and ipratropium (used in the treatment of COPD).<ref name="Purves" /><ref>Template:Cite journal</ref>
In 2024, the United States FDA approved the drug KarXT (Cobenfy), which is a combination drug that combines xanomeline (a preferentially acting M1/M4 muscarinic acetylcholine receptor agonist) with trospium (a peripherally-restricted pan-mAChR antagonist for use in schizophrenia. <ref name=":0">Template:Cite journal</ref> 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 in PANSS 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. <ref name=":0" />
See alsoEdit
- Muscarinic agonist
- Muscarinic antagonist
- Acetylcholine receptor (Cholinergic receptor)
ReferencesEdit
External linksEdit
Template:G protein-coupled receptors Template:Muscarinic acetylcholine receptor modulators