Gene and Protein Information
class A G protein-coupled receptor
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	7	590	1q43	CHRM3	cholinergic receptor muscarinic 3	33
Mouse	7	589	13 3.72 cM	Chrm3	cholinergic receptor, muscarinic 3, cardiac	71
Rat	7	589	17q12.1	Chrm3	cholinergic receptor, muscarinic 3	50,110

Previous and Unofficial Names

HM4 [84-85] | Chrm-3 | M3R | cholinergic receptor, muscarinic 3 | cholinergic receptor | cholinergic receptor, muscarinic 3, cardiac

Database Links
Specialist databases
GPCRdb	acm3_human (Hs), acm3_mouse (Mm), acm3_rat (Rn)
Other databases
Alphafold	P20309 (Hs), Q9ERZ3 (Mm), P08483 (Rn)
ChEMBL Target	CHEMBL245 (Hs), CHEMBL5105 (Mm), CHEMBL320 (Rn)
DrugBank Target	P20309 (Hs)
Ensembl Gene	ENSG00000133019 (Hs), ENSMUSG00000046159 (Mm), ENSRNOG00000049410 (Rn)
Entrez Gene	1131 (Hs), 12671 (Mm), 24260 (Rn)
Human Protein Atlas	ENSG00000133019 (Hs)
KEGG Gene	hsa:1131 (Hs), mmu:12671 (Mm), rno:24260 (Rn)
OMIM	118494 (Hs)
Orphanet	ORPHA299148 (Hs)
Pharos	P20309 (Hs)
RefSeq Nucleotide	NM_000740 (Hs), NM_033269 (Mm), NM_012527 (Rn)
RefSeq Protein	NP_000731 (Hs), NP_150372 (Mm), NP_036659 (Rn)
UniProtKB	P20309 (Hs), Q9ERZ3 (Mm), P08483 (Rn)
Wikipedia	CHRM3 (Hs)

Selected 3D Structures
	Description:  Structure of the M3 Muscarinic Acetylcholine Receptor PDB Id:  4DAJ Ligand:  tiotropium Resolution:  3.4Å Species:  Rat References:  56

Natural/Endogenous Ligands
acetylcholine

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Action Value Parameter Reference [3H]iperoxo Hs Agonist 8.4 pKd 97 ⤷ pKd 8.4 (Kd 3.98x10-9 M) [97] NNC 11-1585 Hs Full agonist 8.3 pKi 20 ⤷ pKi 8.3 [20] NNC 11-1607 Hs Full agonist 8.1 pKi 20 ⤷ pKi 8.1 [20] pentylthio-TZTP Hs Full agonist 8.1 pKi 47 ⤷ pKi 8.1 [47] NNC 11-1314 Hs Full agonist 7.1 – 7.7 pKi 20 ⤷ pKi 7.1 – 7.7 [20] xanomeline Hs Partial agonist 7.2 – 7.4 pKi 88,117,126 ⤷ pKi 7.2 – 7.4 [88,117,126] sabcomeline Hs Partial agonist 7.0 pKi 126 ⤷ pKi 7.0 [126] arecaidine propargyl ester Hs Full agonist 5.7 pKi 47 ⤷ pKi 5.7 [47] acetylcholine Rn Full agonist 5.6 pKi 19 ⤷ pKi 5.6 [19] cevimeline Hs Agonist 5.6 pKi 69 ⤷ pKi 5.6 (Ki 2.575x10-6 M) [69] Description: Displacement of [3H]QNB from cloned receptor. arecoline Hs Full agonist 5.4 pKi 47,82,94 ⤷ pKi 5.4 [47,82,94] oxotremorine Hs Full agonist 5.3 pKi 47,94 ⤷ pKi 5.3 [47,94] McN-A-343 Hs Partial agonist 5.0 – 5.3 pKi 94 ⤷ pKi 5.0 – 5.3 [94] milameline Hs Partial agonist 5.1 pKi 126 ⤷ pKi 5.1 [126] oxotremorine-M Hs Full agonist 5.1 pKi 47 ⤷ pKi 5.1 [47] pilocarpine Hs Partial agonist 5.1 pKi 47,94 ⤷ pKi 5.1 [47,94] acetylcholine Hs Full agonist 4.5 – 5.4 pKi 19,47,51 ⤷ pKi 4.5 – 5.4 [19,47,51] methylfurmethide Hs Full agonist 4.6 pKi 47 ⤷ pKi 4.6 [47] bethanechol Hs Full agonist 4.2 pKi 47,94 ⤷ pKi 4.2 [47,94] carbachol Hs Full agonist 4.0 – 4.4 pKi 19,47,126 ⤷ pKi 4.0 – 4.4 [19,47,126] carbachol Rn Full agonist 4.2 pKi 19 ⤷ pKi 4.2 [19] furtrethonium Hs Full agonist 4.1 pKi 47 ⤷ pKi 4.1 [47] methacholine Rn Agonist 6.9 pEC50 83,94 ⤷ pEC50 6.9 (EC50 1.2x10-7 M) [83,94] (+)-aceclidine Hs Full agonist 5.7 pEC50 29 ⤷ pEC50 5.7 [29] (-)-aceclidine Hs Partial agonist 5.1 pEC50 29 ⤷ pEC50 5.1 [29] iperoxo Hs Agonist - - 97 ⤷ [97] [3H]acetylcholine Hs Agonist - - ⤷
View species-specific agonist tables
Agonist Comments
Please consult references [10,30,62,94,115,124] for further details of the activity of some of the ligands in this list. McN-A-343 has been found to be a partial agonist at the M3 receptor [94,115]. However, in reference [62] it was found to be inactive in a study of GTPase activation. Oxotremorine has been found to be a full agonist [30,94,115] and a partial agonist [62,94] at the M3 receptor.

Antagonists
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Action Value Parameter Reference [3H]tiotropium Hs Antagonist 10.7 pKd 96 ⤷ pKd 10.7 [96] [3H]QNB Hs Antagonist 10.4 pKd 46,85 ⤷ pKd 10.4 (Kd 3.98x10-11 M) [46,85] CHF-6366 Hs Antagonist 10.2 pKd 16 ⤷ pKd 10.2 (Kd 6.3x10-11 M) [16] Description: Binding to human cloned M3 receptor using [3H]-N-methylscopolamine as tracer [3H]N-methyl scopolamine Rn Antagonist 10.0 pKd 19,115 ⤷ pKd 10.0 [19,115] [3H]N-methyl scopolamine Hs Antagonist 9.7 – 10.2 pKd 17,43,46-47,52,60 ⤷ pKd 9.7 – 10.2 (Kd 2.2x10-10 – 6x10-11 M) [17,43,46-47,52,60] [3H]darifenacin Hs Antagonist 9.5 pKd 101 ⤷ pKd 9.5 (Kd 3.16x10-10 M) [101] biperiden Hs Antagonist 8.4 pKd 6 ⤷ pKd 8.4 (Kd 3.9x10-9 M) [6] N-methyl scopolamine Hs Antagonist 10.4 pKi 25 ⤷ pKi 10.4 [25] tiotropium Hs Antagonist 9.5 – 11.1 pKi 24-25,90,107-108 ⤷ pKi 9.5 – 11.1 [24-25,90,107-108] umeclidinium Hs Antagonist 10.2 pKi 57,96 ⤷ pKi 10.2 (Ki 6x10-11 M) [57,96] aclidinium Hs Antagonist 10.1 – 10.2 pKi 90,108 ⤷ pKi 10.1 – 10.2 [90,108] propantheline Hs Antagonist 10.0 pKi 44 ⤷ pKi 10.0 [44] AE9C90CB Hs Antagonist 9.9 pKi 100 ⤷ pKi 9.9 [100] revefenacin Hs Antagonist 9.8 pKi 42 ⤷ pKi 9.8 (Ki 1.78x10-10 M) [42] Description: Determined from a radioligand binding assay using membranes from CHO‐K1 cells expressing the hM3 receptor, and displacement of [3H]NMS tracer. clidinium Hs Antagonist 9.6 pKi 25 ⤷ pKi 9.6 [25] ipratropium Hs Antagonist 9.3 – 9.8 pKi 25,43,90 ⤷ pKi 9.3 – 9.8 [25,43,90] scopolamine Hs Antagonist 9.4 pKi 6,44 ⤷ pKi 9.4 [6,44] 4-DAMP Hs Antagonist 9.3 pKi 27 ⤷ pKi 9.3 [27] 4-DAMP Rn Antagonist 9.2 pKi 50 ⤷ pKi 9.2 [50] atropine Hs Antagonist 8.5 – 9.8 pKi 21,43-44,85 ⤷ pKi 8.5 – 9.8 [21,43-44,85] [3H]4-DAMP Hs Antagonist 8.8 – 9.4 pKi 18,48 ⤷ pKi 8.8 – 9.4 [18,48] dicyclomine Hs Antagonist 9.0 pKi 3 ⤷ pKi 9.0 (Ki 9.3x10-10 M) [3] atropine Rn Antagonist 8.7 – 9.3 pKi 19,50 ⤷ pKi 8.7 – 9.3 [19,50] darifenacin Hs Antagonist 8.9 – 9.1 pKi 37,43,100 ⤷ pKi 8.9 – 9.1 [37,43,100] hexocyclium Hs Antagonist 8.9 pKi 11 ⤷ pKi 8.9 [11] silahexocyclium Hs Antagonist 8.9 pKi 11 ⤷ pKi 8.9 [11] oxybutynin Hs Antagonist 8.8 pKi 23,100 ⤷ pKi 8.8 [23,100] mepenzolic acid Hs Antagonist 8.6 pKi 129 ⤷ pKi 8.6 (Ki 2.6x10-9 M) [129] tolterodine Hs Antagonist 8.4 – 8.5 pKi 37,100 ⤷ pKi 8.4 – 8.5 [37,100] UH-AH 37 Hs Antagonist 8.1 – 8.2 pKi 37,123 ⤷ pKi 8.1 – 8.2 [37,123] p-F-HHSiD Rn Antagonist 8.0 pKi 50 ⤷ pKi 8.0 [50] amitriptyline Hs Antagonist 7.9 pKi 102 ⤷ pKi 7.9 (Ki 1.28x10-8 M) [102] hexahydrosiladifenidol Hs Antagonist 7.7 – 8.0 pKi 11,31 ⤷ pKi 7.7 – 8.0 [11,31] solifenacin Hs Antagonist 7.7 – 8.0 pKi 45,100 ⤷ pKi 7.7 – 8.0 [45,100] hexahydrodifenidol Hs Antagonist 7.8 pKi 11 ⤷ pKi 7.8 [11] p-F-HHSiD Hs Antagonist 7.3 – 7.9 pKi 31,44 ⤷ pKi 7.3 – 7.9 [31,44] dosulepin Hs Antagonist 7.4 pKi 102 ⤷ pKi 7.4 (Ki 3.8x10-8 M) [102] AQ-RA 741 Hs Antagonist 7.2 – 7.3 pKi 27,37 ⤷ pKi 7.2 – 7.3 [27,37] AFDX384 Hs Antagonist 7.2 pKi 27 ⤷ pKi 7.2 [27] himbacine Hs Antagonist 6.9 – 7.2 pKi 27,49,75 ⤷ pKi 6.9 – 7.2 [27,49,75] tropicamide Hs Antagonist 7.0 pKi 21 ⤷ pKi 7.0 [21] (S)-dimetindene Hs Antagonist 6.9 pKi 14 ⤷ pKi 6.9 (Ki 1.38x10-7 M) [14] Description: Binding to hM3 receptors expressed in CHO cells. tripitramine Hs Antagonist 6.8 pKi 76 ⤷ pKi 6.8 [76] pirenzepine Rn Antagonist 6.7 pKi 50 ⤷ pKi 6.7 [50] pirenzepine Hs Antagonist 6.5 – 6.8 pKi 11,27,41,44,49,123 ⤷ pKi 6.5 – 6.8 [11,27,41,44,49,123] methoctramine Hs Antagonist 6.1 – 6.9 pKi 11,27,31,41,101 ⤷ pKi 6.1 – 6.9 [11,27,31,41,101] guanylpirenzepine Rn Antagonist 6.2 pKi 114 ⤷ pKi 6.2 [114] otenzepad Hs Antagonist 6.1 pKi 11 ⤷ pKi 6.1 [11] VU0255035 Hs Antagonist 6.1 pKi 98 ⤷ pKi 6.1 [98] otenzepad Rn Antagonist 6.0 pKi 50 ⤷ pKi 6.0 [50] muscarinic toxin 3 Hs Antagonist <6.0 pKi 49 ⤷ pKi <6.0 [49] lithocholylcholine Hs Antagonist 6.0 pKi 19 ⤷ pKi 6.0 [19] lithocholylcholine Rn Antagonist 6.0 pKi 19 ⤷ pKi 6.0 [19] muscarinic toxin 7 Hs Antagonist <5.0 pKi 78 ⤷ pKi <5.0 [78] ML381 Hs Antagonist <4.5 pKi 36 ⤷ pKi <4.5 (Ki >3x10-5 M) [36] glycopyrrolate Hs Antagonist 9.6 – 9.8 pIC50 105,107 ⤷ pIC50 9.6 – 9.8 [105,107] Description: Assay uses glycopyrronium bromide solifenacin Hs Antagonist 6.9 pIC50 89 ⤷ pIC50 6.9 (IC50 1.308x10-7 M) [89]
View species-specific antagonist tables
Antagonist Comments
Biperiden is an approved drug antagonist of muscarinic acetylcholine receptors. We have tagged the M1 subtype as the drug's primary target as affinity is 10-fold higher at this receptor subtype [6].

Allosteric Modulators
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Action Value Parameter Reference alcuronium Hs Negative 5.8 pKd 47 ⤷ pKd 5.8 [47] vincamine Hs Neutral 5.7 pKd 47 ⤷ pKd 5.7 [47] WIN 51,708 Hs Negative 5.5 pKd 65 ⤷ pKd 5.5 [65] vinburnine Hs Neutral 5.2 pKd 47 ⤷ pKd 5.2 [47] Gö 7874 Hs Negative 5.1 pKd 64 ⤷ pKd 5.1 [64] WIN 62,577 Hs Positive 5.1 pKd 65 ⤷ pKd 5.1 (Kd 7.94x10-6 M) [65] strychnine Hs Negative 4.2 – 5.7 pKd 47,60 ⤷ pKd 4.2 – 5.7 [47,60] thiochrome Hs Neutral 4.4 pKd 61 ⤷ pKd 4.4 [61] N-benzyl brucine Hs Negative 3.8 pKd 63 ⤷ pKd 3.8 [63] N-benzyl brucine Hs Positive 3.8 pKd 63 ⤷ pKd 3.8 [63] brucine Hs Negative 3.6 – 4.0 pKd 47,63 ⤷ pKd 3.6 – 4.0 [47,63] N-chloromethyl-brucine Hs Positive 3.3 pKd 63 ⤷ pKd 3.3 (Kd 5.012x10-4 M) [63] brucine N-oxide Hs Neutral 2.5 pKd 63 ⤷ pKd 2.5 [63] brucine N-oxide Hs Positive 2.5 pKd 63 ⤷ pKd 2.5 [63] VU0119498 Hs Positive 5.2 pEC50 8 ⤷ pEC50 5.2 (EC50 6.38x10-6 M) [8]

Primary Transduction Mechanisms
Transducer	Effector/Response
Gq/G11 family	Phospholipase C stimulation
References:  9,84

Tissue Distribution
Lung. Species:  Human Technique:  Radioligand binding. References:  70
Ciliary muscle. Species:  Human Technique:  In situ hybridisation and Northern blotting. References:  133
Esophageal smooth muscle. Species:  Human Technique:  Radioligand binding. References:  91
Bladder. Species:  Human Technique:  RT-PCR. References:  111
CNS: cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, midbrain, pons-medulla. Species:  Mouse Technique:  Radioligand binding. References:  79
Intestinal smooth muscle. Species:  Rat Technique:  Radioligand binding. References:  15
Heart: intrinsic neurons. Species:  Rat Technique:  in situ hybridisation. References:  40
Gastric smooth muscle. Species:  Rat Technique:  RT-PCR. References:  68
CNS: pons. Species:  Rat Technique:  Radioligand binding. References:  4
CNS: basal forebrain, parabigeminal nucleus, pedunculopontine and laterodorsal tegmental nuclei, cranial nerve nuclei. Species:  Rat Technique:  in situ hybridisation. References:  112
CNS: cerebral cortex, hippocampu, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum. Species:  Rat Technique:  Immunoprecipitation. References:  130
CNS: hippocampus. Species:  Rat Technique:  immunocytochemistry. References:  67
CNS: limbic cortical regions, striatum, hippocampus, anterior thalamic nuclei, superior colliculus, pontine nuclei. Species:  Rat Technique:  immunocytochemistry. References:  66
Vestibular system. Species:  Rat Technique:  RT-PCR. References:  113
Salivary gland: striated and interlobular duct cells. Species:  Rat Technique:  Immunohistochemistry. References:  99

Expression Datasets
Show »« Hide Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website] There should be a chart of expression data here, you may need to enable JavaScript!

Functional Assays
Measurement of IP levels in isolated rat ventricular cardiomyocytes. Species:  Rat Tissue:  Isolated ventricular cardiomyocytes. Response measured:  Stimulation of IP formation. References:  92
Measurement of PI hydrolysis in CHO cells transfected with the human M3 receptor. Species:  Human Tissue:  CHO cells. Response measured:  Stimulation of PI hydrolysis. References:  20
Measurement of IP3 levels in CHO cells transfected with the rat M3 receptor. Species:  Rat Tissue:  CHO cells. Response measured:  Stimulation of IP3 accumulation. References:  19
Measurement of IP1 levels in murine fibroblast cells (B82) transfected with the rat M3 receptor. Species:  Rat Tissue:  B82 cells. Response measured:  Stimulation of IP1 accumulation. References:  50
Measurement of cAMP and Ca2+ levels in rat parotid cells endogenously expressing the M3 receptor. Species:  Rat Tissue:  Parotid cells. Response measured:  Inhibition of cAMP accumulation and stimulation of Ca2+ mobilisation. References:  80
Measurement of IP levels in CHO cells transfected with the human M3 receptor. Species:  Human Tissue:  CHO cells. Response measured:  Stimulation of IP accumulation. References:  94,118
Measurement of IP levels in human right atrial slices. Species:  Human Tissue:  Atrial slices. Response measured:  Stimulation of IP formation. References:  125
Measurement of neuronal nitric oxide synthetase activity in CHO cells transfected with the M3 receptor. Species:  Human Tissue:  CHO cells. Response measured:  Increase in NO synthetase activity. References:  116
Measurement of ERK1/2 activity in COS-7 cells transfected with the human M3 receptor. Species:  Human Tissue:  COS-7 cells. Response measured:  Increase in ERK1/2 activity. References:  95
Measurement of ERK1/2 activity in CHO cells transfected with the human M3 receptor. Species:  Human Tissue:  CHO cells. Response measured:  Increase in ERK1/2 activity. References:  12
Measurement of ERK1/2 activity in human SK-N-BE2(C) cells endogenously expressing the M3 receptor. Species:  Human Tissue:  SK-N-BE2(C) cells. Response measured:  Increase in ERK1/2 activity. References:  54
Measurement of the effects of a ligand on the level, or rate, of binding of GTPγ35S to membranes. Species:  Human Tissue:  CHO cells. Response measured:  The binding of GTPγ35S to G proteins coupled to the receptor. References:  5,59-62,64-65
Measurement of the effects of a ligand on the rate of hydrolysis of GTP by G proteins in membranes. Species:  Human Tissue:  CHO cell membranes. Response measured:  Generation of 32Pi from [γ-32P]GTP. References:  62

Physiological Functions
Vasodilation. Species:  Rat Tissue:  Thoracic aortic rings. References:  53
Vasodilation Species:  Mouse Tissue:  Thoracic aortic rings. References:  53
Stimulation of pancreatic insulin and glucagon release. Species:  Mouse Tissue:  In vivo. References:  26
Bronchoconstriction. Species:  Rat