Muscarinic acetylcholine receptor M3

Protein and coding gene in humans

CHRM3

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes
2CSA

Identifiers

Aliases

CHRM3, EGBRS, HM3, PBS, cholinergic receptor muscarinic 3

External IDs

OMIM: 118494 MGI: 88398 HomoloGene: 20191 GeneCards: CHRM3

Gene location (Human)

Chr.	Chromosome 1 (human)^[1]

Band	1q43	Start	239,386,565 bp^[1]
Band	1q43	End	239,915,452 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 13 (mouse)^[2]

Band	13 A1\|13 3.72 cM	Start	9,925,522 bp^[2]
Band	13 A1\|13 3.72 cM	End	10,410,883 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

endothelial cell

Brodmann area 23

middle temporal gyrus

parotid gland

postcentral gyrus

superior frontal gyrus

entorhinal cortex

orbitofrontal cortex

Brodmann area 46

frontal pole

Top expressed in

superior frontal gyrus

urethra

pretectal area

tongue

secondary oocyte

pharynx

larynx

hippocampus proper

primary motor cortex

stomach

More reference expression data

BioGPS

n/a

Gene ontology
Molecular function	G protein-coupled receptor activity acetylcholine binding signal transducer activity protein binding phosphatidylinositol phospholipase C activity G protein-coupled acetylcholine receptor activity signaling receptor activity G protein-coupled serotonin receptor activity neurotransmitter receptor activity
Cellular component	axon terminus integral component of membrane postsynaptic membrane membrane synapse integral component of plasma membrane cell junction basolateral plasma membrane dendrite asymmetric synapse plasma membrane glutamatergic synapse integral component of presynaptic membrane integral component of postsynaptic density membrane
Biological process	smooth muscle contraction G protein-coupled acetylcholine receptor signaling pathway G protein-coupled receptor signaling pathway saliva secretion nervous system development adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway regulation of vasoconstriction phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway cell population proliferation positive regulation of smooth muscle contraction regulation of vascular associated smooth muscle contraction signal transduction synaptic transmission, cholinergic G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger chemical synaptic transmission G protein-coupled serotonin receptor signaling pathway positive regulation of vascular associated smooth muscle contraction
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


1131


12671

Ensembl


ENSG00000133019


ENSMUSG00000046159

UniProt


P20309


Q9ERZ3

RefSeq (mRNA)

NM_000740 NM_001347716 NM_001375978 NM_001375979 NM_001375980
NM_001375981 NM_001375982 NM_001375983 NM_001375984 NM_001375985


NM_033269

RefSeq (protein)

NP_000731 NP_001334645 NP_001362907 NP_001362908 NP_001362909
NP_001362910 NP_001362911 NP_001362912 NP_001362913 NP_001362914


NP_150372

Location (UCSC)

Chr 1: 239.39 – 239.92 Mb

Chr 13: 9.93 – 10.41 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M₃, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.^[5]

The M₃ muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands, lungs, pancreas and the brain. In the CNS, they induce emesis. Muscarinic M₃ receptors are expressed in regions of the brain that regulate insulin homeostasis, such as the hypothalamus and dorsal vagal complex of the brainstem.^[6] These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion.^[7] In general, they cause smooth muscle contraction and increased glandular secretions.^[5]

They are unresponsive to PTX and CTX.

Mechanism

Like the M₁ muscarinic receptor, M₃ receptors are coupled to G proteins of class G_q, which upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway.^[8] The calcium function in vertebrates also involves activation of protein kinase C and its effects.

Effects

Smooth muscle

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 and vasodilation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M₃ mediates vasoconstriction in pathologies wherein the vascular endothelium is disrupted.^[9]

Diabetes

The muscarinic M₃ receptor regulates insulin secretion from the pancreas^[7] and are an important target for understanding the mechanisms of type 2 diabetes mellitus.

Some antipsychotic drugs that are prescribed to treat schizophrenia and bipolar disorder (such as olanzapine and clozapine) have a high risk of diabetes side-effects. These drugs potently bind to and block the muscarinic M₃ receptor, which causes insulin dysregulation that may precede diabetes.^[6]

Other

The M₃ receptors are also located in many glands, both endocrine and exocrine glands, and help to stimulate secretion in salivary glands and other glands of the body.

Other effects are:

increased secretions from stomach
eye accommodation

Agonists

No highly selective M3 agonists are yet available as of 2018, but a number of non-selective muscarinic agonists are active at M3.

acetylcholine
bethanechol
carbachol^[10]
L-689,660 (mixed M1/M3 agonist)
oxotremorine^[10]
pilocarpine (in eye)
muscarine

Antagonists

aclidinium bromide
4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4)
darifenacin
diphenhydramine
fluoxetine
DAU-5884 (8-Methyl-8-azabicyclo-3-endo[1.2.3]oct-3-yl-1,4-dihydro-2-oxo-3(2H)-quinazolinecarboxylic acid ester, CAS# 131780-47-7)
HL-031,120 ((3R,2'R)-enantiomer of EA-3167)
ipratropium^[10]
J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide, CAS# 244277-89-2)
oxybutynin^[10]
procyclidine
tiotropium
tolterodine^[10]
zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)
solifenacin

Interactions

Muscarinic acetylcholine receptor M3 has been shown to pre-couple with Gq proteins. The polybasic c-tail of the receptor is necessary for the pre-coupling.^[8] It has also been shown to interact with Arf6^[13] and ARF1.^[13]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000133019 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000046159 - Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3".
^ ^a ^b Weston-Green K, Huang XF, Lian J, Deng C (May 2012). "Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels". European Neuropsychopharmacology. 22 (5): 364–373. doi:10.1016/j.euroneuro.2011.09.003. PMID 21982116. S2CID 31739607.
^ ^a ^b Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, et al. (June 2006). "A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo". Cell Metabolism. 3 (6): 449–461. doi:10.1016/j.cmet.2006.04.009. hdl:10533/177761. PMID 16753580.
^ ^a ^b ^c Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology. 7 (10): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
^ 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.
^ ^a ^b ^c ^d ^e ^f Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. pp. 139. ISBN 0-443-07145-4.
^ Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A (November 2002). "The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors". Anesthesia and Analgesia. 95 (5): 1269–73, table of contents. doi:10.1097/00000539-200211000-00031. PMID 12401609. S2CID 39621215.
^ Edwards Pharmaceuticals, Inc., Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved January 13, 2013.
^ ^a ^b Mitchell R, Robertson DN, Holland PJ, Collins D, Lutz EM, Johnson MS (September 2003). "ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor". The Journal of Biological Chemistry. 278 (36): 33818–33830. doi:10.1074/jbc.M305825200. PMID 12799371.

External links

"Acetylcholine receptors (muscarinic): M₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2013-11-03. Retrieved 2008-11-25.
Overview of all the structural information available in the PDB for UniProt: P20309 (Human Muscarinic acetylcholine receptor M3) at the PDBe-KB.
Overview of all the structural information available in the PDB for UniProt: P08483 (Rat Muscarinic acetylcholine receptor M3) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3
Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)
Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)
Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin (1A 1B 1C) TAAR (1 2 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 1 2 FPRL1 OXE Prostaglandin DP (1 2), EP (1 2 3 4), FP Prostacyclin Thromboxane
Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Hydroxycarboxylic acids 1 2 3 Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide

B/W (1
2)
FF (1
2)
S
Y (1
2
4
5)
Neuromedin (B
U (1
2))
Neurotensin (1
2)

Other

Anaphylatoxin (C3a
C5a (1
2))
Angiotensin (1
2)
Apelin
Bombesin
- BRS3
- GRPR
- NMBR)
- Bradykinin (B1
- B2)
Chemokine
Cholecystokinin (A
B)
Endothelin
- A
- B
Formyl peptide (1
2
3)
FSH
Galanin (1
2
3)
Gonadotropin-releasing hormone (1
2)
Ghrelin
Kisspeptin
Luteinizing hormone/choriogonadotropin
MAS (1
1L
D
E
F
G
X1
X2
X3
X4)
Melanocortin (1
2
3
4
5)
MCHR (1
2)
Motilin
Opioid (Delta
Kappa
Mu
Nociceptin & Zeta, but not Sigma)
Orexin (1
2)
Oxytocin
Prokineticin (1
2)
Prolactin-releasing peptide
Relaxin (1
2
3
4)
Somatostatin (1
2
3
4
5)
Tachykinin (1
2
3)
Thyrotropin
Thyrotropin-releasing hormone
Urotensin-II
Vasopressin (1A
1B
2)

Miscellaneous

Taste, bitter	TAS2R 1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60 Vomeronasal receptor type 1
Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)
Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin-like

Adhesion	ADGRB Brain-specific angiogenesis inhibitor 1 2 3 ADGRC Cadherin 1 2 3 ADGRE EMR 1 2 3 CD97 ADGRG 1 2 3 4 5 6 7 ADGRL Latrophilin 1 2 3 ELTD1
Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)
Other	Calcitonin CALCRL Corticotropin-releasing hormone (1 2) Glucagon (GR GIPR GLP1R GLP2R) Growth-hormone-releasing hormone PACAPR1 GPR Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste, sweet	TAS1R 1 2 3 Vomeronasal receptor, type 2
Other	Calcium-sensing receptor GABA_B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)