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M3

Previous and Unofficial Names
Names References
m3
HM4 6,23
Structural Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Name Reference
Human 7 590 1q41-q44 CHRM3 152
Rat 7 589 17q12.1 Chrm3 3,84
Mouse 7 589 13 A1 Chrm3 9
Contents:
Previous and Unofficial Names
Structural Information
Database Links
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Receptor Comments
Database Links
ChEMBL Target 219 (Hs), 10649 (Mm), 12566 (Rn)
Ensembl ENSG00000133019 (Hs), ENSMUSG00000046159 (Mm), ENSRNOG00000014639 (Rn)
Entrez Gene 1131 (Hs), 12671 (Mm), 24260 (Rn)
GeneCards CHRM3 (Hs)
HomoloGene 20191 (Hs)
OMIM 118494 (Hs)
PharmGKB Gene PA112 (Hs)
Protein Ontology (PRO) PRO:000001615 (Hs)
RefSeq Nucleotide NM_000740 (Hs), NM_033269 (Mm), NM_012527 (Rn)
RefSeq Protein NP_000731 (Hs), NP_150372 (Mm), NP_036659 (Rn)
UniGene Hs. 7138 (Hs)
UniProt P20309 (Hs), Q9ERZ3 (Mm), P08483 (Rn)
Wikipedia M3
Search for 3D structures on the PDB
Search using keywords: Acetylcholine receptors (muscarinic) M3 Search using accession numbers: P08483 || P20309 || Q9ERZ3
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
NNC 11-1585 Hs Full agonist 8.3 pKi 39
NNC 11-1607 Hs Full agonist 8.1 pKi 39
pentylthio-TZTP Hs Full agonist 8.1 pKi 80
NNC 11-1314 Hs Full agonist 7.1 – 7.7 pKi 39
xanomeline Hs Partial agonist 7.2 – 7.4 pKi 1,82
sabcomeline Hs Partial agonist 7.0 pKi 82
arecaidine propargyl ester Hs Full agonist 5.7 pKi 80
acetylcholine Rn Full agonist 5.6 pKi 79
arecoline Hs Full agonist 5.4 pKi 80
oxotremorine Hs Full agonist 5.3 pKi 80
McN-A-343 Hs Partial agonist 5.0 – 5.3 pKi 11
milameline Hs Partial agonist 5.1 pKi 82
oxotremorine-M Hs Full agonist 5.1 pKi 80
pilocarpine Hs Partial agonist 5.1 pKi 80
acetylcholine Hs Full agonist 4.5 – 5.4 pKi 46,79-80
methylfurmethide Hs Full agonist 4.6 pKi 80
bethanechol Hs Full agonist 4.2 pKi 80
carbachol Hs Full agonist 4.0 – 4.4 pKi 79-80,82
carbachol Rn Full agonist 4.2 pKi 79
furmethide Hs Full agonist 4.1 pKi 80
(+)aceclidine Hs Full agonist 5.7 pEC50 76
(-)aceclidine Hs Partial agonist 5.1 pEC50 76
View species-specific agonist tables
Agonist Comments
Please consult references [10-14,153] 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 [11-12]. However, in reference [10] it was found to be inactive in a study of GTPase activation.
Oxotremorine has been found to be a full agonist [11-12,153] and a partial agonist [10-11] at the M3 receptor.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]QNB Hs Antagonist 10.4 pKd 6
[3H]NMS Rn Antagonist 10.0 pKd 12,79
[3H]darifenacin Hs Antagonist 9.5 pKd 96
[3H]NMS Hs Antagonist 8.6 – 10.4 pKd 46,79-80,85,90,92-94
tiotropium Hs Antagonist 11.1 pKi 184
N-methyl scopolamine Hs Antagonist 10.4 pKi 184
propantheline Hs Antagonist 10.0 pKi 85
clidinium Hs Antagonist 9.6 pKi 184
ipratropium Hs Antagonist 9.3 – 9.8 pKi 92,184
scopolamine Hs Antagonist 9.4 pKi 85
atropine Hs Antagonist 8.9 – 9.8 pKi 6,85,87,92,96,184
4-DAMP Rn Antagonist 9.2 pKi 84
darifenacin Hs Antagonist 9.1 pKi 92
atropine Rn Antagonist 8.7 – 9.3 pKi 79,84
hexocyclium Hs Antagonist 8.9 pKi 87
silahexocyclium Hs Antagonist 8.9 pKi 87
p-F-HHSiD Rn Antagonist 8.0 pKi 84
HHSiD Hs Antagonist 7.7 – 8.0 pKi 86-87
hexahydrodifenidol Hs Antagonist 7.8 pKi 87
p-F-HHSiD Hs Antagonist 7.3 – 7.9 pKi 85-86
himbacine Hs Antagonist 6.9 – 7.2 pKi 90,97
pirenzepine Rn Antagonist 6.7 pKi 84
methoctramine Hs Antagonist 6.3 – 6.9 pKi 86-87,96
pirenzepine Hs Antagonist 5.6 – 6.7 pKi 6,85-87,90
AF-DX 116 Hs Antagonist 6.1 pKi 86-87
AF-DX 116 Rn Antagonist 6.0 pKi 84
lithocholylcholine Hs Antagonist 6.0 pKi 79
lithocholylcholine Rn Antagonist 6.0 pKi 79
View species-specific antagonist tables
Allosteric Regulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
alcuronium Hs Negative 5.8 pKd 80
vincamine Hs Neutral 5.7 pKd 80
WIN 51,708 Hs Negative 5.5 pKd 49
eburnamonine Hs Neutral 5.2 pKd 80
Gö 7874 Hs Negative 5.1 pKd 48
WIN 62,577 Hs Positive 5.1 pKd 49
strychnine Hs Negative 4.2 – 5.7 pKd 46,80
thiochrome Hs Neutral 4.4 pKd 50
brucine Hs Negative 3.6 – 4.0 pKd 80,98
N-benzyl brucine Hs Positive 3.8 pKd 98
N-benzyl brucine Hs Negative 3.8 pKd 98
N-chloromethyl-brucine Hs Negative 3.3 pKd 98
N-chloromethyl-brucine Hs Positive 3.3 pKd 98
brucine N-oxide Hs Neutral 2.5 pKd 98
brucine N-oxide Hs Positive 2.5 pKd 98

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
References:  22-23
Tissue Distribution
Lung.
Species:  Human
Technique:  Radioligand binding.
References:  174
CNS: hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  62
CNS: limbic cortical regions, striatum, hippocampus, anterior thalamic nuclei, superior colliculus, pontine nuclei.
Species:  Rat
Technique:  immunocytochemistry.
References:  175
Salivary gland: striated and interlobular duct cells.
Species:  Rat
Technique:  Immunohistochemistry.
References:  129
Vestibular system.
Species:  Rat
Technique:  RT-PCR.
References:  55
Ciliary muscle.
Species:  Human
Technique:  In situ hybridisation and Northern blotting.
References:  130
Esophageal smooth muscle.
Species:  Human
Technique:  Radioligand binding.
References:  56
Bladder.
Species:  Human
Technique:  RT-PCR.
References:  57
Gastric smooth muscle.
Species:  Rat
Technique:  RT-PCR.
References:  176
CNS: pons.
Species:  Rat
Technique:  Radioligand binding.
References:  52
CNS: basal forebrain, parabigeminal nucleus, pedunculopontine and laterodorsal tegmental nuclei, cranial nerve nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  59
CNS: cerebral cortex, hippocampu, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum.
Species:  Rat
Technique:  Immunoprecipitation.
References:  60
Intestinal smooth muscle.
Species:  Rat
Technique:  Radioligand binding.
References:  131
CNS: cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, midbrain, pons-medulla.
Species:  Mouse
Technique:  Radioligand binding.
References:  61
Heart: intrinsic neurons.
Species:  Rat
Technique:  in situ hybridisation.
References:  54
Functional Assays
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:  11,169
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:  79
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:  84
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:  168
Measurement of IP levels in human right atrial slices.
Species:  Human
Tissue:  Atrial slices.
Response measured:  Stimulation of IP formation.
References:  170
Measurement of IP levels in isolated rat ventricular cardiomyocytes.
Species:  Rat
Tissue:  Isolated ventricular cardiomyocytes.
Response measured:  Stimulation of IP formation.
References:  171
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:  39
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:  42
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:  43
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:  172
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:  173
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:  10,45-50
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:  10
Physiological Functions
Vasodilation.
Species:  Rat
Tissue:  Thoracic aortic rings.
References:  164
Vasodilation
Species:  Mouse
Tissue:  Thoracic aortic rings.
References:  164
Stimulation of pancreatic insulin and glucagon release.
Species:  Mouse
Tissue:  In vivo.
References:  163
Bronchoconstriction.
Species:  Rat
Tissue:  Isolated lung.
References:  177
Modulation of salivary gland function.
Species:  Rat
Tissue:  In vivo.
References:  178
Modulation of excitatory transmission.
Species:  Rat
Tissue:  Mesencephalic slices.
References:  179
Gastric acid secretion.
Species:  Rat
Tissue:  Gastric parietal cells.
References:  180
Modulation of insulin secretion.
Species:  Rat
Tissue:  Isolated pancreatic islets.
References:  181
Vasodilation.
Species:  Rat
Tissue:  Pulmonary artery.
References:  132
Stimulation of urination.
Species:  Rat
Tissue:  In vivo.
References:  74
Contraction.
Species:  Human
Tissue:  Urinary bladder detrusor muscle.
References:  182
Contraction.
Species:  Rat
Tissue:  Urinary bladder detrusor muscle.
References:  183
Contraction.
Species:  Human
Tissue:  Esophageal smooth muscle.
References:  56
Contraction.
Species:  Rat
Tissue:  Ileum.
References:  131
Physiological Consequences of Altering Gene Expression
M3 receptor knockout mice exhibit impaired gastric acid secretion.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  159-160
M3 receptor knockout mice show reduced adiposity and serum insulin and leptin levels, and exhibit reduced food intake.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  154
Lung slices from M3 receptor knockout mice exhibit reduced agonist-induced bronchoconstriction compared to wild-type mice.
This bronchoconstriction is completely abolished in M2/M3 double knockout mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  35
M3 receptor knockout mice exhibit abolished agonist-induced or vagally-stimulated bronchoconstriction in vivo.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  120
Isolated coronary arteries and aortic rings from M3 receptor knockout mice exhibit a reduction in agonist-induced dilation compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  155
M3 receptor knockout mice exhibit alterations in paradoxical sleep.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  156
M3 receptor knockout mice exhibit growth retardation, increased pupil size and reduced salivary secretion.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  157
Striatal slices from M3 receptor knockout mice exhibit an increase in muscarinic agonist-induced potentiation of dopamine release.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  158
M3 receptor knockout mice exhibit abolished agonist-induced PLC activation and insulin secretion from pancreatic islets.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  161
M3 receptor knockout mice exhibit altered ventilatory pattern and chemosensitivity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  36
M3 receptor knockout mice exhibit impaired salivation.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  162
M3 receptor knockout mice exhibit abolished agonist-induced pancreatic insulin and glucagon release as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  163
M3 receptor knockout mice exhibit reduced gastric pepsinogen secretion.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  32
Thoracic aortic rings from M3 receptor knockout mice exhibit reduced agonist-induced relaxation compared to those from wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  164
Transgenic mice overexpressing the M3 receptor in pancreatic β-cells exhibit increased glucose tolerance and insulin release. They are resistant to diet-induced glucose intolerance and hyperglycemia.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  165
Mice that selectively lack the M3 receptor in pancreatic β-cells exhibit decreased glucose tolerance and impaired insulin release.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  165
M3 receptor knockout mice express an increase in basal and total energy expenditure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  166
Smooth muscle preparations (gallbladder, urinary bladder, stomach fundus, trachea, ileum) from M3 receptor knockout mice exhibit reduced agonist-induced contractions compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  113,118,157,167
Smooth muscle preparations (gallbladder, urinary bladder, stomach fundus, trachea) from M3 receptor knockout mice exhibit reduced agonist-induced contractions compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  113,157,167
Receptor Comments
For reviews on muscarinic receptor knockout mice see [15-19].

To cite this receptor data page, please use the following:

Nigel J. M. Birdsall, David A. Brown, Noel J. Buckley, Arthur Christopoulos, Richard M. Eglen, Frederick Ehlert, Rudolf Hammer, Heinz J. Kilbinger, Günter Lambrecht, Fred Mitchelson, Ernst Mutschler, Neil M. Nathanson, Roy D. Schwarz, Andrew B. Tobin, Jurgen Wess.
Acetylcholine receptors (muscarinic): M3. Last modified on 2010-06-28. Accessed on 2010-09-03. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=15.


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