Muscarinic acetylcholine receptor

Amanita muscaria, the mushroom from which muscarine was isolated.

Acetylcholine - the natural agonist of muscarinic and nicotinic receptors.

Muscarine - an agonist used to distinguish between these two classes of receptors. Not normally found in the body.

Atropine - an antagonist.

Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons^[1] 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 were named as such because they are more sensitive to muscarine than to nicotine.^[2] 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.^[3]

Function

Acetylcholine (ACh) is a neurotransmitter found extensively in the brain and autonomic nervous system and it is the only neurotransmitter used at the neuromuscular junction. Muscarinic receptors are used in the following roles:

Recovery receptors

ACh is always used as the transmitter 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 with their corresponding adrenergic receptors, or cholinergic fibers with their cholinergic receptors. Both preganglionic sympathetic fibers and preganglionic parasympathetic fibers are cholinergic. All postganglionic sympathetic fibers are adrenergic; their neurotransmitter is norepinephrine, except for the postganglionic sympathetic fibers to the sweat glands, piloerectile muscles of the body hairs and the skeletal muscle arterioles.

The adrenal medulla is considered a sympathetic ganglion and like other sympathetic ganglia, is supplied by cholinergic preganglionic sympathetic fibers; acetylcholine is its neurotransmitter. The other postganglionic fibers of the peripheral autonomic system belong to the parasympathetic division; all are cholinergic fibers, and use acetylcholine (ACh) as their neurotransmitter.

ACh has two types of effects. The first type is termed muscarinic, which is the parasympathetic effect on the secretory exocrine glands, and on smooth and cardiac muscles through their corresponding receptors. The other type of ACh effect is termed nicotinic, which is on the skeletal (voluntary) muscles; it is not considered to be part of the peripheral autonomic nervous system.

Postganglionic neurons

Another role for these receptors is at the junction of the innervated tissue and the postganglionic neuron 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

By contrast, this junction in the sympathetic division mostly does not use acetylcholine as a neurotransmitter; instead, norepinephrine is used. Therefore neither muscarinic nor nicotinic receptors are involved, but adrenergic α₁ and β₁ receptors. Very few parts of the sympathetic system use cholinergic receptors (some postganglionic fibers terminating on sweat glands, which release acetylcholine, and in the kidney, which release dopamine are of the few exceptions). 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 acetylcholine at the junction between its one peripheral nerve and the innervated tissue, also of the nicotinic type.

Higher central nervous system

Muscarinic acetylcholine receptors are also present and distributed throughout the central 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 junction

It's now known they 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 metabotropic receptors that use G proteins as their signalling mechanism. In such receptors, the signaling molecule (the ligand) binds to a 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.

By contrast, nicotinic receptors use an ion-gated 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 type(s) of ion (e.g., K⁺, Na⁺, Ca⁺²) 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).^[4] 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 has proceeded in numerical order: therefore, sources that recognize only the M₁/M₂ distinction exist. More recent studies tend to recognize M₃ and the most recent M₄.

Genetic differences

Meanwhile, geneticists and molecular biologists have characterised five genes that appear to encode muscarinic receptors, named m1-m5 (lowercase m; no subscript number). The first four code for pharmacologic types M₁-M₄. The fifth, M₅, corresponds to a subtype of receptor that had until recently not been detected pharmacologically. 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 proteins

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: G_s, G_i, G_q, and G_12/13.^[5] 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). G_s and some subtypes of G_i (G_αt and G_αg) are susceptible to CTX. Only G_i is susceptible to PTX, with the exception of one subtype of G_i (G_αz) which is immune. Also, only when bound with an agonist, those G proteins normally sensitive to PTX also become susceptible to CTX.^[6]

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[7]	Antagonists[7]
M1	CHRM1	EPSP in autonomic ganglia secretion from salivary glands and stomach In CNS (memory?)[8]	no (yes)	no (yes)	Gq (Gi) (Gs): Slow EPSP. ↓ K+ conductance[8][9]	acetylcholine oxotremorine muscarine carbachol[8] McNA343[8] 77-LH-28-1	atropine[8] scopolamine[8] dicycloverine[8] tolterodine[8] oxybutynin[8] ipratropium[8] mamba toxin MT7[8] pirenzepine telenzepine
M2	CHRM2	*slow heart rate reduce contractile forces of atrium reduce conduction velocity of AV node In CNS homotropic inhibition	yes	no	Gi ↑ K+ conductance[8] ↓ Ca2+ conductance[8]	acetylcholine methacholine carbachol[8] oxotremorine[8] muscarine	atropine[8] dicycloverine[8] tolterodine[8] oxybutynin[8] ipratropium[8] methoctramine[10] tripitramine gallamine
M3	CHRM3	smooth muscle contraction Increase intracellular calcium in vascular endothelium increased endocrine and exocrine gland secretions, e.g. salivary glands and stomach In CNS Eye accommodation vasodilation induce emesis	no	no	Gq	acetylcholine bethanechol carbachol[8] oxotremorine[8] pilocarpine (in eye)	atropine[8] dicycloverine[8] tolterodine[8] oxybutynin[8] ipratropium[8] darifenacin tiotropium
M4	CHRM4	Activation of M4 causes decreased locomotion[8] In CNS	yes	?	Gi ↑ K+ conductance[8] ↓ Ca2+ conductance[8]	acetylcholine carbachol[8] oxotremorine[8]	atropine[8] dicycloverine[8] tolterodine[8] oxybutynin[8] ipratropium[8] mamba toxin MT3[8]
M5	CHRM5	In CNS	no	?	Gq	acetylcholine carbachol[8] oxotremorine[8]	atropine[8] dicycloverine[8] tolterodine[8] oxybutynin[8] ipratropium[8]

M₁ receptor

Main article: Muscarinic acetylcholine receptor M1

This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve,^[11] is common in exocrine glands and in the CNS.^[12][13]

It is predominantly found bound to G proteins of class G_q,^[14] 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, G_i (causing a downstream decrease in cAMP) and G_s (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

Main article: Muscarinic acetylcholine receptor M2

The M₂ muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after stimulatory actions of the sympathetic nervous system, by slowing the speed of depolarization. They also 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 G_i type receptor, which causes a decrease in cAMP in the cell, inhibition of voltage-gated Ca²⁺ channels, and efflux of K⁺, in general, leading to inhibitory-type effects.

M₃ receptor

Main article: Muscarinic acetylcholine receptor M3

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 G_q-coupled and mediates an increase in intracellular calcium, it typically causes constriction of smooth muscle, such as that observed during bronchoconstriction. 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 vasconstriction in pathologies wherein the vascular endothelium is disrupted.^[15] 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 G_q that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.

M₄ receptor

Main article: Muscarinic acetylcholine receptor M4

M₄ receptors are found in the CNS.

Receptors work via G_i receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects.

M₅ receptor

Main article: Muscarinic acetylcholine receptor M5

Location of M₅ receptors is not well known.

Like the M₁ and M₃ muscarinic receptor, M₅ receptors are coupled with G proteins of class G_q that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.

Pharmacological application

Ligands targeting the mAChR that are currently approved for clinical use include non-selective antagonists for the treatment of Parkinson's disease,^[16] atropine (to dilate the pupil), Scopolamine (used to prevent motion sickness), and ipratropium (used in the treatment of COPD).^[3]

See also

• Nicotinic acetylcholine receptor
• Muscarinic receptor agonist
• Tiotropium
• Nicotinic agonist

References

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2. ^ Ishii M, Kurachi Y (2006). "Muscarinic acetylcholine receptors". Curr. Pharm. Des. 12 (28): 3573–81. doi:10.2174/138161206778522056. PMID 17073660. http://www.bentham-direct.org/pages/content.php?CPD/2006/00000012/00000028/0002B.SGM. 
3. ^ ^{a b} Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed.. Sinauer Associates. pp. 122–6. ISBN 978-0-87893-697-7. 
4. ^ Caulfield MP, Birdsall NJ (1 June 1998). "International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors". Pharmacol. Rev. 50 (2): 279–90. PMID 9647869. http://pharmrev.aspetjournals.org/content/50/2/279.short. 
5. ^ Simon MI, Strathmann MP, Gautam N (1991). "Diversity of G proteins in signal transduction". Science 252 (5007): 802–8. doi:10.1126/science.1902986. PMID 1902986. 
6. ^ Dell'Acqua ML, Carroll RC, Peralta EG (15 March 1993). "Transfected m2 muscarinic acetylcholine receptors couple to G alpha i2 and G alpha i3 in Chinese hamster ovary cells. Activation and desensitization of the phospholipase C signaling pathway". J. Biol. Chem. 268 (8): 5676–85. PMID 8449930. http://www.jbc.org/cgi/content/abstract/268/8/5676. 
7. ^ ^{a b} Tripathi KD (2004). Essentials of Medical Pharmacology (5th ed.). India: Jaypee Brothers, Medical Publishers. pp. 890 pages. ISBN 81-8061-187-6.  if nothing else mentioned in table
8. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as} Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. pp. 139. ISBN 0-443-07145-4. 
9. ^ Uchimura N, North RA (1990). "Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones". J. Physiol. (Lond.) 422 (1): 369–80. PMC 1190137. PMID 1693682. http://jp.physoc.org/cgi/content/abstract/422/1/369. 
10. ^ Melchiorre C, Angeli P, Lambrecht G (1987). "Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine" European Journal of Pharmacology, http://www.sciencedirect.com/science/article/pii/0014299987905097
11. ^ Messer, Jr, WS (2000-01-20). "Acetylcholine". University of Toledo. http://www.neurosci.pharm.utoledo.edu/MBC3320/acetylcholine.htm. Retrieved 2007-10-27. 
12. ^ Johnson, Gordon (2002). PDQ Pharmacology (2nd ed.). Hamilton, Ontario: BC Decker Inc. pp. 311 pages. ISBN 1-55009-109-3. 
13. ^ Richelson, Elliott (2000). "Cholinergic Transduction, Psychopharmacology - The Fourth Generation of Progress". American College of Neuropsychopharmacology. http://www.acnp.org/g4/GN401000011/Default.htm. Retrieved 2007-10-27. 
14. ^ Burford NT, Nahorski SR (1996). "Muscarinic M₁ receptor-stimulated adenylate cyclase activity in Chinese hamster ovary cells is mediated by Gs alpha and is not a consequence of phosphoinositidase C activation". Biochem. J. 315 ( Pt 3): 883–8. PMC 1217289. PMID 8645172. http://www.biochemj.org/bj/315/bj3150883.htm. 
15. ^ Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred (2006). Goodman & Gilman's the pharmacological basis of therapeutics (11th ed.). New York: McGraw-Hill. pp. 185. ISBN 0-07-142280-3. 
16. ^ Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacol. Ther. 117 (2): 232–43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893. 

External links

• "Acetylcholine Receptors (Muscarinic)". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1271. 
• MeSH Receptors,+Muscarinic