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Acetylcholine receptors (muscarinic)

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* Receptor family under development

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Copyright © 2007 IUPHAR

Acetylcholine receptors (muscarinic) last modified on 2007-06-21 10:56:51.0

M₂

Previous Names
Names	References
m2

Database Links
Entrez Gene	1129
HomoloGene	20190
UniGene Hs.	527965
GeneCards	CHRM2
OMIM	118493

Structural Information
class A G protein-coupled receptor
Species	TM	AA	Accession Number	Chromosomal Location	Gene Name	References
Human	7	466	P08172	7q31-q35	CHRM2	2, 5, 69, 91, 92
Rat	7	466	P10980	4q22	Chrm2	107
Mouse	7	466	Q9ERZ4	6 B1	Chrm2	95

Functional Assays
Measurement of cAMP levels in CHO cells transfected with the human M2 receptor. Species:  Human Tissue:  CHO cells. Response measured:  Inhibition of cAMP accumulation. References:  21, 98, 115, 239
Measurement of cAMP levels in mouse Y1 adrenal cells transfected with the mouse M2 receptor. Species:  Mouse Tissue:  Y1 adrenal cells. Response measured:  Inhibition of cAMP accumulation. References:  94
Measurement of cAMP levels in JEG-3 cells transfected with the human M2 receptor, using a cAMP response element (CRE)-coupled luciferase construct as the reporter. Species:  Human Tissue:  JEG-3 cells. Response measured:  Inhibition of cAMP accumulation. References:  114
Measurement of cAMP levels in dissociated rat cortical tissue endogenously expressing the M2 receptor. Species:  Rat Tissue:  Cortical tissue. Response measured:  Inhibition of cAMP accumulation. References:  160
Measurement of ERK1/2 activity in COS-7 cells transfected with the human M2 receptor. Species:  Human Tissue:  COS-7 cells. Response measured:  Increase in ERK1/2 activity. References:  256
Measurement of GIRK channel activity in Xenopus oocytes transfected with the human M2 receptor. Species:  Human Tissue:  Xenopus oocytes. Response measured:  Activation of GIRK channels. References:  261
Measurement of GIRK channel activity in rat superior cervical ganglion neurons endogenously expressing the M2 receptor. Species:  Rat Tissue:  Superior cervical ganglion neurons. Response measured:  Activation of GIRK channels. References:  76, 262
Measurement of AC activity in rat myocardial homogenates endogenously expressing the M2 receptor. Species:  Rat Tissue:  Myocardial homogenates. Response measured:  Inhibition of AC activity. References:  273
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:  19, 20, 25, 30, 244, 251, 279
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:  20

Agonists
Click column headers to sort
Click here for key Ligand Action Affinity Units Reference       Hs (+)aceclidine Full Agonist 6.4-6.2 pEC50 266, 274       Hs (-)aceclidine Partial Agonist 5.7-5.6 pEC50 266, 274   Rn acetylcholine Full Agonist 6.4 pKi 100   Hs acetylcholine Full Agonist 6.5-4.3 pKi 25, 28, 98, 100       Hs arecaidine propargyl ester Full Agonist 5.7 pKi 28     Hs arecoline Full Agonist 5.2 pKi 28     Hs bethanechol Full Agonist 4.0 pKi 28     Hs carbachol Full Agonist 5.7-4.2 pKi 28, 98, 100     Rn carbachol Full Agonist 5.7 pKi 100       Hs furmethide Full Agonist 4.5 pKi 28     Rn McN-A-343 Partial Agonist 6.0-4.7 pKi 291       Hs methylfurmethide Full Agonist 4.9 pKi 28       Hs NNC 11-1314 Full Agonist 7.2 pKi 239       Hs NNC 11-1585 Full Agonist 10.1 pKi 239       Hs NNC 11-1607 Full Agonist 8.2 pKi 239     Rn oxotremorine Full Agonist 6.5 pKi 100     Hs oxotremorine Full Agonist 6.6-5.0 pKi 28, 100     Hs oxotremorine-M Full Agonist 4.9 pKi 28       Hs pentylthio-TZTP Full Agonist 7.9 pKi 28     Hs pilocarpine Partial Agonist 4.9 pKi 28     Hs xanomeline Full Agonist 7.4-6.9 pKi 143, 290
Agonist Comments: The binding data for McN-A-343 [291] is found on rat heart. Please consult references [20,21,265,286,288] for further details of the activity of some of the ligands in this list. Pilocarpine has been found to be a partial agonist [20,288] and a full agonist [265] at the M2 receptor.

Antagonists
Click column headers to sort
Click here for key Ligand Action Affinity Units Reference       Rn [3H](-)MQNB Antagonist 9.5 pKd 100       Hs [3H](-)MQNB Antagonist 9.6 pKd 100       Rn [3H]4NMPB Antagonist 9.4 pKd 96     Hs p-F-HHSiD Antagonist 6.6-6.1 pKi 104, 268     Hs AF-DX 116 Antagonist 7.3-6.7 pKi 100, 101, 268     Rn AF-DX 116 Antagonist 7.3-4.6 pKi 96, 100, 113       Hs [3H]AF-DX 384 Antagonist 8.7 pKd 149     Hs atropine Antagonist 9.2-7.8 pKi 5, 97, 98, 100, 101, 104, 106     Rn atropine Antagonist 9.1-9.0 pKi 100, 113       Hs 4-DAMP Antagonist 8.3 pKi 100     Rn 4-DAMP Antagonist 8.2 pKi 100, 113     Hs darifenacin Inverse Agonist 7.6-7.3 pKi 97, 106       Hs dexetimide Antagonist 8.9 pKi 100       Rn dexetimide Antagonist 8.8 pKi 100       Hs dicyclomine Antagonist 6.6 pKi 101     Hs gallamine Antagonist 5.8 pKi 100     Rn gallamine Antagonist 5.6 pKi 100     Hs hexahydrodifenidol Antagonist 6.7 pKi 101     Hs hexocyclium Antagonist 7.6 pKi 101     Rn HHSiD Antagonist 6.8-6.7 pKi 100, 113     Hs HHSiD Antagonist 6.8-6.6 pKi 100, 101, 268     Hs himbacine Antagonist 8.4-7.9 pKi 17, 100, 146       Rn himbacine Antagonist 7.9 pKi 100       Hs imipramine Antagonist 6.9 pKi 100     Hs ipratropium Antagonist 8.8 pKi 97       Hs levetimide Antagonist 5.0 pKi 100       Rn levetimide Antagonist 4.8 pKi 100       Hs lithocholylcholine Antagonist 5.4 pKi 98     Rn methoctramine Antagonist 7.3 pKi 100     Hs methoctramine Antagonist 8.4-7.3 pKi 100, 101, 106, 268     Hs [3H]NMS Antagonist 9.9-6.3 pKd 17, 25, 28, 97, 98, 102, 115, 144, 265     Rn [3H]NMS Antagonist 9.5 pKd 96       Hs oxybutynin Inverse Agonist 7.7 pKi 106     Hs pirenzepine Antagonist 6.4-4.9 pKi 5, 17, 100, 101, 104, 106, 268     Rn pirenzepine Antagonist 7.4-5.3 pKi 96, 100, 113     Hs propantheline Antagonist 9.5 pKi 104     Hs [3H]QNB Antagonist 10.6-10.1 pKd 5         Hs SCH 57790 Antagonist 8.6 pKi 145     Hs scopolamine Antagonist 8.7 pKi 104     Hs silahexocyclium Antagonist 7.5 pKi 101       Hs tolterodine Inverse Agonist 8.6 pKi 106       Hs tripitramine Antagonist 9.6 pKi 99
Antagonist Comments: Dexetimide is the optical isomer of levetimide [100].

Allosteric Regulators
Click column headers to sort
Click here for key Ligand Action Affinity Units Reference       Hs N-benzyl brucine Positive 4.8 pKd 29       Hs N-benzyl brucine Negative 4.8 pKd 29     Hs alcuronium Neutral 6.9-6.1 pKd 28, 253     Hs brucine Negative 4.3 pKd 29     Hs brucine Positive 4.6-4.3 pKd 28, 29       Hs brucine N-oxide Negative 3.5 pKd 29       Hs brucine N-oxide Positive 3.5 pKd 29       Hs chloromethylbrucine Negative 4.6 pKd 29       Hs chloromethylbrucine Positive 4.6 pKd 29         Hs dimethyl-W84 Positive 8.5 pKi 253       Hs [3H]dimethyl-W84 Positive 8.5 pKi 253     Hs eburnamonine Neutral 4.2 pKd 28     Rn gallamine Negative 5.6 pKi 100     Hs gallamine Negative 7.6-5.8 pKi 100, 253       Hs Go 7874 Negative 5.0 pKd 244       Hs KT 5823 Positive 5.7 pKd 244       Hs staurosporine Positive 5.1 pKd 244     Hs strychnine Positive 5.0-4.9 pKd 25, 28, 253     Hs thiochrome Neutral 3.9 pKd 279     Hs vincamine Neutral 5.1 pKd 28       Hs W-84 Positive 7.6 pKi 253         Hs WDuo3 Positive 6.9 pKi 253       Hs WIN 51708 Negative 5.9 pKd 251       Hs WIN 62577 Negative 5.3 pKd 251

Primary Transduction Mechanisms
Transducer	Effector/Response
Gi/G0 family	Adenylate cyclase inhibition
Comments:
References: 114, 269

Secondary Transduction Mechanisms
Transducer	Effector/Response
Gs family Gq/G11 family	Adenylate cyclase stimulation Phospholipase C stimulation
Comments:
References: 236, 274

Receptor Distribution
CNS: caudate putamen. Species:  Rat Technique:  in situ hybridisation. References:  11
CNS: pons. Species:  Rat Technique:  Radioligand binding. References:  237
CNS: forebrain. Species:  Mouse Technique:  immunocytochemistry. References:  238
Heart: intrinsic neurons. Species:  Rat Technique:  in situ hybridisation. References:  227
Salivary gland: submandibular ganglion. Species:  Rat Technique:  Immunohistochemistry. References:  230
Vestibular system. Species:  Human Technique:  RT-PCR. References:  231
Vestibular system. Species:  Rat Technique:  RT-PCR. References:  231
Ciliary muscle. Species:  Human Technique:  In situ hybridisation and Northern blotting. References:  232
CNS: cerebral cortex, thalamus, brainstem, medulla, hypothalamus. Species:  Human Technique:  Radioligand binding. References:  141
Esophageal smooth muscle. Species:  Human Technique:  Radioligand binding. References:  233
Bladder. Species:  Human Technique:  RT-PCR. References:  234
CNS: basal forebrain, parabigeminal nucleus, pedunculopontine and laterodorsal tegmental nuclei, cranial nerve nuclei. Species:  Rat Technique:  in situ hybridisation. References:  38
CNS: cerebral cortex, hipocampus, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum. Species:  Rat Technique:  Immunoprecipitation. References:  270
CNS: cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, midbrain, pons-medulla, cerebellum, spinal cord. Species:  Mouse Technique:  Radioligand binding. References:  271
Intestinal smooth muscle. Species:  Rat Technique:  Radioligand binding. References:  275
CNS: hippocampus. Species:  Rat Technique:  immunocytochemistry. References:  228

Tissue Function
Vasodilation. Species:  Rat Tissue:  Pulmonary artery. References:  121
Mediation of colonic motor responses to eating. Species:  Human Tissue:  In vivo. References:  140
Hypertension. Species:  Rat Tissue:  In vivo. References:  150
Stimulation of pancreatic secretion. Species:  Rat Tissue:  In vivo. References:  151
Stimulation of water consumption. Species:  Rat Tissue:  In vivo. References:  152
Control of small intestinal motility. Species:  Rat Tissue:  In vivo. References:  153
Hypotension. Species:  Rat Tissue:  In vivo. References:  155
Bradycardia. Species:  Rat Tissue:  In vivo. References:  155
Thermal automodulator. Species:  Rat Tissue:  In vivo. References:  156
Autoreceptor: modulation of ACh release. Species:  Human Tissue:  Bronchi. References:  157, 158
Stimulation of histamine release. Species:  Rat Tissue:  Stomach. References:  159
Spinal analgesia. Species:  Rat Tissue:  In vivo. References:  161
Autoreceptor: modulation of ACh release. Species:  Rat Tissue:  Heart. References:  162
Locomotor activity. Species:  Rat Tissue:  In vivo. References:  164
Modulation of the sleep-wake cycle. Species:  Rat Tissue:  In vivo. References:  192-194

Physiological Consequences of Altering Gene Expression
Atrial preparations from M2 receptor knockout mice do not exhibit agonist-induced bradycardia as seen in wild-type atrial preparations. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  55, 56, 165
M2 receptor knockout mice do not exhibit agonist-induced tremor as seen in wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  55
M2 receptor knockout mice exhibit reduced agonist-induced hypothermia as compared to wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  55
M2 receptor knockout mice exhibit reduced agonist-induced antinociception compared to wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  55, 169
Smooth muscle preparations (stomach fundus, urinary bladder, trachea, gallbladder) from M2 receptor knockout mice exhibit reduced agonist-induced contractions compared to wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  56, 165, 167
Hippocampal, cortical and striatal brain slices from M2/M4 double knockout mice lack muscarinic agonist-induced inhibition of acetylcholine release that is seen with wild-type brain slices. From M2 receptor single knockout mice, the hippocampal and cortical slices exhibit this loss of inhibition of acetylcholine release, but the inhibition remains in the striatal slices. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  166
Skin preparations from M2 receptor knockout mice no longer show muscarinic-induced desensitisation of peripheral nociception. In addition, the heat-induced release of CGRP which is inhibited by muscarine in wild-type mice is unaltered in M2 knockout mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  168
Tissue from atria, bladder and vas deferens of M2 receptor knockout mice exhibit reduced agonist-induced inhibition of noradrenaline release compared to wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  170
Smooth muscle preparations (ileum, trachea, urinary bladder) from M2 receptor knockout mice exhibit increased relaxant effects of forskolin and isoproterenol against agonist-induced contractions. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  171, 276
M2 receptor knockout mice exhibit a reduced muscarinic antagonist-induced increase in hippocampal acetylcholine release compared to wild-type mice. M2/M4 double knockout mice completely lack this response. In addition, M2 and M2/M4 knockout mice exhibit an increase in hippocampal acetylcholine release in response to a novel environment. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  172
Lung slices from M2 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 Technique  Gene targeting in embryonic stem cells. References:  173
M2 receptor knockout mice do not exhibit agonist-induced or vagally-stimulated bradycardia in vivo as seen in wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  174
M2 receptor knockout mice exhibit increased agonist-induced or vagally-stimulated bronchoconstriction in vivo compared to wild-type mice. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  174
M2 receptor knockout mice exhibit impaired behavioural flexibility, working memory and hippocampal plasticity. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  176
M2 receptor knockout mice exhibit increased agonist/stress-induced pituitary-adrenal responses. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  178
Smooth muscle from the small intestine of M2 receptor knockout mice do not exhibit any alteration in EFS-induced acetylcholine release. However, M2/M4 double knockout mice exhibit an increase in acetylcholine release. Overall, it is thought that both M2 and M4 receptors mediate the autoinhibitory control of acetylcholine release in the mouse ileum, and that each can compensate for loss of the other. Species:  Mouse Technique  Gene targeting in embryonic stem cells. References:  205

Comments
For reviews on muscarinic receptor knockout mice see [209-212,272].

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