Muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are
Muscarinic receptors are so named because they are more sensitive to
Function
Recovery receptors
Peripheral autonomic fibers (sympathetic and parasympathetic fibers) are categorized anatomically as either preganglionic or
The
Postganglionic neurons
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 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
The
Higher central nervous system
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
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.
Form of muscarinic receptors
Muscarinic acetylcholine receptors belong to a class of
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 isoforms
Classification
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).[5] M1, M3, M5 receptors are coupled with Gq proteins, while M2 and M4 receptors are coupled with Gi/o proteins.[4] 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,[citation needed] while later studies recognize M3, M4,[1] and most recently M5 subtypes.[citation needed]
Genetic differences
Meanwhile,
Difference in 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.[6] 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.[7]
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[8] | Antagonists[8] |
---|---|---|---|---|---|---|---|
M1 | CHRM1 | no (yes) |
no (yes) |
Gq (Gi) (Gs): Slow EPSP. ↓ K+ conductance[11][15] |
|||
M2 | CHRM2 |
|
yes | no | Gi ↑ K+ conductance[11] ↓ Ca2+ conductance[11] |
| |
M3 | CHRM3 |
|
no | no | Gq |
| |
M4 | CHRM4 |
|
yes | ? | Gi ↑ K+ conductance[11] ↓ Ca2+ conductance[11] |
| |
M5 | CHRM5 |
|
no | ? | Gq |
M1 receptor
This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve[citation needed], is common in exocrine glands and in the CNS.[23][24]
It is predominantly found bound to G proteins of class Gq,[25] 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 receptor
The M2 muscarinic receptors are located in the heart and lungs. In the heart, they act to slow the
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 receptor
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
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.[4]
M4 receptor
M4 receptors are found in the CNS.
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 receptor
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.[citation needed]
Pharmacological application
See also
- Muscarinic agonist
- Muscarinic antagonist
- Nicotinic acetylcholine receptor
- Nicotinic agonist
- Nicotinic antagonist
- Vagal escape
References
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- PMID 17073660. Archived from the originalon 2009-02-05. Retrieved 2020-04-10.
- ^ ISBN 978-0-87893-697-7.)
{{cite book}}
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- ^ ISBN 978-81-8061-187-2. if nothing else mentioned in table
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- ^ ISBN 978-0-443-07145-4.
- ^ PMID 30252390, retrieved 7 January 2020
- ^ PMID 16751797.
- ^ PMID 11482763.
- PMID 1693682. Archived from the originalon 2009-01-30. Retrieved 2008-02-25.
- PMID 2041225.
- PMID 17583355.
- ^ a b c Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved January 13, 2013.
{{cite journal}}
: Cite journal requires|journal=
(help) - ^ a b
Servent D, Blanchet G, Mourier G, Marquer C, Marcon E, Fruchart-Gaillard C (November 2011). "Muscarinic toxins". Toxicon. 58 (6–7): 455–63. PMID 21906611.
- ^ PMID 11086210.
- ^ Human Metabolome Database, HMDB. 5.0.
- PMID 3436364.
- ISBN 978-1-55009-109-0.
- ^ Richelson, Elliott (2000). "Cholinergic Transduction, Psychopharmacology - The Fourth Generation of Progress". American College of Neuropsychopharmacology. Retrieved 2007-10-27.
- PMID 8645172.
- PMID 22001099.
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- PMID 18082893.
- PMID 25413004.
External links
- Acetylcholine Receptors (Muscarinic)
- Receptors,+Muscarinic at the U.S. National Library of Medicine Medical Subject Headings (MeSH)