image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

M4 receptor

Family: Acetylcholine receptors (muscarinic)

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 479 11p12-p11.2 CHRM4 cholinergic receptor, muscarinic 4 2,23
Mouse 7 479 2 E1 Chrm4 cholinergic receptor, muscarinic 4 42
Rat 7 478 3q32-q35 Chrm4 cholinergic receptor, muscarinic 4 31,61,73
Previous and Unofficial Names
Names References
m4
HM3 52-53
acetylcholine receptor, muscarinic 4
cholinergic receptor, muscarin 4
muscarinic acetylcholine receptor M4
Chrm-4
muscarinic acetylcholine receptor 4
Database Links
ChEMBL Target 214 (Hs), 10687 (Mm), 12485 (Rn)
DrugBank Target 450 (Hs)
Ensembl ENSG00000180720 (Hs), ENSMUSG00000040495 (Mm), ENSRNOG00000017556 (Rn)
Entrez Gene 1132 (Hs), 12672 (Mm), 25111 (Rn)
GeneCards CHRM4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Chrm4 (Mm)
HomoloGene 20192 (Hs)
Human Protein Reference Database 00330 (Hs)
InterPro P08173 (Hs), P32211 (Mm), P08485 (Rn)
KEGG Gene hsa:1132 (Hs), mmu:12672 (Mm), rno:25111 (Rn)
OMIM 118495 (Hs)
PharmGKB Gene PA26485 (Hs)
PhosphoSitePlus P08173 (Hs), P32211 (Mm), P08485 (Rn)
Protein Ontology (PRO) PRO:000001616 (Hs)
RefSeq Nucleotide NM_000741 (Hs), NM_007699 (Mm), NM_031547 (Rn)
RefSeq Protein NP_000732 (Hs), NP_031725 (Mm), NP_113735 (Rn)
TreeFam ENSG00000180720 (Hs), ENSMUSG00000040495 (Mm), ENSRNOG00000017556 (Rn)
UniGene Hs. 248100 (Hs)
UniProt P08173 (Hs), P32211 (Mm), P08485 (Rn)
Wikipedia M4 receptor
Acetylcholine receptors (muscarinic)
Search for 3D structures on the PDB
Search by keyword: Acetylcholine receptors (muscarinic) M4 receptor Search by accession number: P08485, P08173, P32211
Natural/Endogenous Ligand(s)
acetylcholine
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
pentylthio-TZTP Hs Full agonist 8.7 pKi 29
NNC 11-1585 Hs Full agonist 8.6 pKi 11
NNC 11-1607 Hs Full agonist 8.1 pKi 11
xanomeline Hs Partial agonist 7.4 – 7.7 pKi 68,74
NNC 11-1314 Hs Full agonist 7.3 pKi 11
sabcomeline Hs Partial agonist 7.2 pKi 74
McN-A-343 Hs Partial agonist 5.6 – 6.7 pKi 33
arecaidine propargyl ester Hs Full agonist 5.9 pKi 29
arecoline Hs Full agonist 5.5 pKi 29
milameline Hs Partial agonist 5.5 pKi 74
oxotremorine Hs Full agonist 5.2 pKi 29
oxotremorine-M Hs Full agonist 5.2 pKi 29
pilocarpine Hs Partial agonist 5.2 pKi 29
acetylcholine Hs Full agonist 4.5 – 5.6 pKi 7,29,35
methylfurmethide Hs Full agonist 4.7 pKi 29
carbachol Hs Full agonist 4.3 – 4.9 pKi 29,74
furmethide Hs Full agonist 4.3 pKi 29
bethanechol Hs Full agonist 4.0 pKi 29
(+)aceclidine Hs Full agonist 5.4 pEC50 17
(-)aceclidine Hs Partial agonist 4.8 pEC50 17
Agonist Comments
The binding data for McN-A-343 [33] is found on rat striatum.
Please consult references [3,37,55,67] for further details of the activity of some of the ligands in this list.
McN-A-343 and pilocarpine have been found to be partial agonists [37] and full agonists [55,67] at the M4 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 9.7 – 10.5 pKd 10,53
[3H]N-methyl scopolamine Hs Antagonist 7.8 – 10.2 pKd 6-7,10,26,29-30,32,35,49,67
[3H]AF DX-384 Hs Antagonist 8.6 pKd 46
propantheline Hs Antagonist 10.2 pKi 28
atropine Rn Antagonist 9.7 pKi 31
scopolamine Hs Antagonist 9.5 pKi 28
ipratropium Hs Antagonist 9.2 pKi 26
4-DAMP Rn Antagonist 9.1 pKi 31
atropine Hs Antagonist 8.7 – 9.5 pKi 4,26,28,53
4-DAMP Hs Antagonist 8.9 pKi 15
MT3 Hs Antagonist 8.7 pKi 30,49
silahexocyclium Hs Antagonist 8.5 pKi 4
hexocyclium Hs Antagonist 8.3 pKi 4
darifenacin Hs Antagonist 8.1 pKi 26
himbacine Hs Antagonist 7.9 – 8.2 pKi 30,45
AFDX384 Hs Antagonist 8.0 pKi 15
AF-DX 116 Hs Antagonist 7.0 – 8.7 pKi 4,18
HHSiD Rn Antagonist 7.7 pKi 31
p-F-HHSiD Hs Antagonist 7.1 – 7.5 pKi 18,28
hexahydrodifenidol Hs Antagonist 7.1 pKi 4
HHSiD Hs Antagonist 6.5 – 7.7 pKi 4,18
MT1 Hs Antagonist 7.1 pKi 24
pirenzepine Rn Antagonist 7.1 pKi 31
methoctramine Hs Antagonist 6.6 – 7.0 pKi 4,18
pirenzepine Hs Antagonist 5.9 – 7.6 pKi 4,18,28,30,53
AF-DX 116 Rn Antagonist 6.5 pKi 31
guanylpirenzepine Rn Antagonist 6.2 pKi 66
MT2 Hs Antagonist 5.9 pKi 24
VU0255035 Hs Antagonist 5.9 pKi 57
lithocholylcholine Hs Antagonist 5.3 pKi 7
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
KT 5720 Hs Neutral 6.4 pKd 39
WIN 51,708 Hs Negative 6.2 pKd 40
WIN 62,577 Hs Negative 5.9 pKd 40
Gö 7874 Hs Neutral 5.7 pKd 39
alcuronium Hs Negative 5.6 pKd 29
brucine Hs Negative 4.7 – 6.0 pKd 29,38
staurosporine Hs Neutral 5.3 pKd 39
strychnine Hs Positive 4.8 – 5.0 pKd 29,35
eburnamonine Hs Positive 4.6 pKd 29
N-benzyl brucine Hs Neutral 4.5 pKd 38
N-benzyl brucine Hs Negative 4.5 pKd 38
N-chloromethyl-brucine Hs Neutral 4.4 pKd 38
vincamine Hs Positive 4.2 pKd 29
thiochrome Hs Positive 4.0 pKd 36
brucine N-oxide Hs Neutral 3.6 pKd 38
brucine N-oxide Hs Positive 3.6 pKd 38

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

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References:  44,52
Tissue Distribution
Bladder.
Species:  Human
Technique:  RT-PCR.
References:  62
Esophageal smooth muscle.
Species:  Human
Technique:  Radioligand binding.
References:  54
CNS: forebrain.
Species:  Mouse
Technique:  immunocytochemistry.
References:  27
CNS: cerebral cortex, corpus striatum, thalamus, hypothalamus, pons-medulla.
Species:  Mouse
Technique:  Radioligand binding.
References:  47
Vestibular system.
Species:  Rat
Technique:  RT-PCR.
References:  65
CNS: cerebral cortex, hippocampus, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum.
Species:  Rat
Technique:  Immunoprecipitation.
References:  75
CNS: hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  41
CNS: basal forebrain, pedunculopontine and laterodorsal tegmental nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  64
CNS: caudate putamen, nucleus accumbens, olfactory tubercle.
Species:  Rat
Technique:  in situ hybridisation.
References:  69
Heart: intrinsic neurons.
Species:  Rat
Technique:  in situ hybridisation.
References:  25
Expression Datasets

Click here to show/hide data

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 IP1 levels in murine fibroblast cells (B82) transfected with the rat M4 receptor.
Species:  Rat
Tissue:  B82 cells.
Response measured:  Stimulation of IP1 accumulation.
References:  31
Measurement of cAMP levels in murine fibroblast cells (B82) transfected with the rat M4 receptor.
Species:  Rat
Tissue:  B82 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  31
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:  44
Measurement of cAMP levels in CHO cells transfected with the human M4 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  11
Measurement of ERK1/2 activity in COS-7 cells transfected with the human M4 receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Increase in ERK1/2 activity.
References:  56
Measurement of Ca2+ channel activity in rat superior cervical ganglion neurons endogenously expressing the M4 receptor.
Species:  Rat
Tissue:  Superior cervical ganglion neurons.
Response measured:  Inhibition of Ca2+ channels.
References:  19-20
Measurement of AC activity in rat striatal homogenates endogenously expressing the M4 receptor.
Species:  Rat
Tissue:  Corpus striatum.
Response measured:  Inhibition of AC activity.
References:  16,48
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:  1,34-37,39-40
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:  1,37
Physiological Functions
Autoreceptor: modulation of acetylcholine release.
Species:  Rat
Tissue:  Urinary bladder.
References:  12
Autoreceptor: modulation of acetylcholine release.
Species:  Human
Tissue:  Urinary bladder detrusor muscle.
References:  13
Contraction.
Species:  Rat
Tissue:  Urinary bladder detrusor muscle.
References:  51
Inhibition of dopaminergic (D1 receptor) signalling.
Species:  Rat
Tissue:  Nucleus accumbens.
References:  50
Cell migration.
Species:  Human
Tissue:  Keratinocytes.
References:  9
Physiological Consequences of Altering Gene Expression
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.
Striatal slices from M4 receptor single knockout mice exhibit the same loss of inhibition of acetylcholine release, but the inhibition remains intact in the hippocampal and cortical slices.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  76
Smooth muscle preparations (gallbladder) from M4 receptor knockout mice exhibit reduced agonist-induced contractions compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  58
Vas deferens tissue from M4 receptor knockout mice exhibits reduced agonist-induced inhibition of noradrenaline release compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  60
Striatal slices from M4 receptor knockout mice exhibit abolished agonist-induced potentiation of dopamine release.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  77
M4 receptor knockout mice exhibit enhanced dopaminergic locomotor activity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  21-22
Epidermal keratinocytes from M4 receptor knockout mice exhibit reduced agonist-induced migration compared to keratinocytes from wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  9
M4 receptor knockout mice exhibit increased basal hippocampal acetylcholine levels compared to wild-type mice.
M2/M4 double knockout mice exhibit a further increase in basal acetylcholine levels.
In addition, M4 and M2/M4 knockout mice exhibit an increase in hippocampal acetylcholine release in response to a novel environment.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  63
M4 receptor knockout mice exhibit a significantly reduced wound epithelialisation rate compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  8
Smooth muscle from the small intestine of M4 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
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  59
M4 receptor knockout mice exhibit an increase in anxiolysis compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  14
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Chrm4tm1Minm Chrm4tm1Minm/Chrm4tm1Minm
involves: 129X1/SvJ * DBA/2J		 MGI:88399  MP:0009745 abnormal behavioral response to xenobiotic PMID: 12729838 
Chrm2tm1Jwe|Chrm4tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S4/SvJae * 129S6/SvEvTac * CF-1		 MGI:88397  MGI:88399  MP:0004994 abnormal brain wave pattern PMID: 16110248 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88399  MP:0002206 abnormal CNS synaptic transmission PMID: 15919709 
Chrm1tm1Jwe|Chrm4tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MGI:88399  MP:0002206 abnormal CNS synaptic transmission PMID: 15919709 
Chrm2tm1Jwe|Chrm4tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S4/SvJae * 129S6/SvEvTac * CF-1		 MGI:88397  MGI:88399  MP:0002206 abnormal CNS synaptic transmission PMID: 15919709 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88399  MP:0005085 abnormal gallbladder physiology PMID: 11961069 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88399  MP:0001629 abnormal heart rate PMID: 10688600 
Chrm4tm1Minm Chrm4tm1Minm/Chrm4tm1Minm
involves: 129X1/SvJ * DBA/2J		 MGI:88399  MP:0001392 abnormal locomotor activity PMID: 12729838 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0004811 abnormal neuron physiology PMID: 20147565 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
B6.129S6-Chrm4		 MGI:88399  MP:0001529 abnormal vocalization PMID: 18382674 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0002822 catalepsy PMID: 20147565 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88399  MP:0001262 decreased body weight PMID: 10468635 
Chrm1tm1Jwe|Chrm4tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MGI:88399  MP:0002917 decreased synaptic depression PMID: 15919709 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0009749 enhanced behavioral response to addictive substance PMID: 20147565 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0009754 enhanced behavioral response to cocaine PMID: 20147565 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0009746 enhanced behavioral response to xenobiotic PMID: 20147565 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88399  MP:0001399 hyperactivity PMID: 10468635 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0001399 hyperactivity PMID: 20147565 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0009747 impaired behavioral response to xenobiotic PMID: 20147565 
Chrm4tm1Jwe Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88399  MP:0000740 impaired smooth muscle contractility PMID: 11961069 
Chrm4tm2.1Jwe|Tg(Drd1a-cre)AGsc Chrm4tm2.1Jwe/Chrm4tm2.1Jwe,Tg(Drd1a-cre)AGsc/0
involves: 129S6/SvEvTac * C57BL/6 * FVB/N		 MGI:3761815  MGI:88399  MP:0001906 increased dopamine level PMID: 20147565 
General Comments
For reviews on muscarinic receptor knockout mice see [5,43,70-72].

REFERENCES

Show »

1. Birdsall, N. J. M., Farries, T., Gharagozloo, P., Kobayashi, S., Lazareno, S. and Sugimoto, M. (1999) Subtype selective positive cooperative interactions between brucine analogues and acetylcholine at muscarinic receptors: functional studies. Mol. Pharmacol., 55: 778-786. [PMID:10101037]

2. Bonner, T. I., Modi, W. S., Seuanez, H. N. and O'Brien, S. J. (1991) Chromosomal mapping of the five human genes encoding muscarinic acetylcholine receptors. Cytogenet. Cell Genet., 58: 1850-1851.

3. Bräuner-Osborne, H., Ebert, B., Brann, M. R., Falch, E. and Krogsgaard-Larsen, P. (1996) Functional partial agonism at cloned human muscarinic acetylcholine receptors. Eur J Pharmacol, 313: 145-150. [PMID:8905341]

4. Buckley, N. J., Bonner, T. I., Buckley, C. M. and Brann, M. R. (1989) Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol, 35: 469-476. [PMID:2704370]

5. Bymaster, F. P., McKinzie, D. L., Felder, C. C. and Wess, J. (2003) Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem Res, 28: 437-442. [PMID:12675128]

6. Cembala, T. M., Sherwin, J. D., Tidmarsh, M. D., Appadu, B. L. and Lambert, D. G. (1998) Interaction of neuromuscular blocking drugs with recombinant human m1-m5 muscarinic receptors expressed in Chinese hamster ovary cells. Br J Pharmacol, 125: 1088-1094. [PMID:9846649]

7. Cheng, K., Khurana, S., Chen, Y., Kennedy, R. H., Zimniak, P. and Raufman, J. P. (2002) Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. J Pharmacol Exp Ther, 303: 29-35. [PMID:12235229]

8. Chernyavsky, A. I., Arredondo, J., Wess, J., Karlsson, E. and Grando, S. A. (2004) Novel signaling pathways mediating reciprocal control of keratinocyte migration and wound epithelialization through M3 and M4 muscarinic receptors. J Cell Biol, 166: 261-272. [PMID:15263021]

9. Chernyavsky, A. I., Nguyen, V. T., Arredondo, J., Ndoye, A., Zia, S., Wess, J. and Grando, S. A. (2003) The M4 muscarinic receptor-selective effects on keratinocyte crawling locomotion. Life Sci, 72: 2069-2073. [PMID:12628458]

10. Christopoulos, A. and Wilson, K. (2001) Interaction of anandamide with the M(1) and M(4) muscarinic acetylcholine receptors. Brain Res, 915: 70-78. [PMID:11578621]

11. Christopoulos, A., Grant, M. K., Ayoubzadeh, N., Kim, O. N., Sauerberg, P., Jeppesen, L. and El-Fakahany, E. E. (2001) Synthesis and pharmacological evaluation of dimeric muscarinic acetylcholine receptor agonists. J Pharmacol Exp Ther, 298: 1260-1268. [PMID:11504829]

12. D'Agostino, G., Barbieri, A., Chiossa, E. and Tonini, M. (1997) M4 muscarinic autoreceptor-mediated inhibition of [3H]acetylcholine release in the rat isolated urinary bladder. J. Pharmacol. Exp. Ther., 283: 750-756. [PMID:9353395]

13. D'Agostino, G., Bolognesi, M. L., Lucchelli, A., Vicini, D., Balestra, B., Spelta, V., Melchiorre, C. and Tonini, M. (2000) Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: involvement of the M4 subtype. Br. J. Pharmacol., 129: 493-500. [PMID:10711347]

14. Degroot, A. and Nomikos, G. G. (2006) Genetic deletion of muscarinic M4 receptors is anxiolytic in the shock-probe burying model. Eur J Pharmacol, 531: 183-186. [PMID:16455072]

15. Dörje, F; Wess, J; Lambrecht, G; Tacke, R; Mutschler, E; Brann, MR. (1991) Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J. Pharmacol. Exp. Ther., 256 (2): 727-33. [PMID:1994002]

16. Ehlert, F. J., Delen, F. M., Yun, S. H., Friedman, D. J. and Self, D. W. (1989) Coupling of subtypes of the muscarinic receptor to adenylate cyclase in the corpus striatum and heart. J Pharmacol Exp Ther, 251: 660-671. [PMID:2810116]

17. Ehlert, F. J., Griffin, M. T. and Glidden, P. F. (1996) The interaction of the enantiomers of aceclidine with subtypes of the muscarinic receptor. J Pharmacol Exp Ther, 279: 1335-1344. [PMID:8968358]

18. Esqueda, E. E., Gerstin, E. H., Griffin, M. T. and Ehlert, F. J. (1996) Stimulation of cyclic AMP accumulation and phosphoinositide hydrolysis by M3 muscarinic receptors in the rat peripheral lung. Biochem Pharmacol, 52: 643-658. [PMID:8759038]

19. Fernandez-Fernandez, J. M., Abogadie, F. C., Milligan, G., Delmas, P. and Brown, D. A. (2001) Multiple pertussis toxin-sensitive G-proteins can couple receptors to GIRK channels in rat sympathetic neurons when expressed heterologously, but only native G(i)-proteins do so in situ. Eur J Neurosci, 14: 283-292. [PMID:11553279]

20. Fernandez-Fernandez, J. M., Wanaverbecq, N., Halley, P., Caulfield, M. P. and Brown, D. A. (1999) Selective activation of heterologously expressed G protein-gated K+ channels by M2 muscarinic receptors in rat sympathetic neurones. J. Physiol., 515: 631-637. [PMID:10066893]

21. Gomeza, J., Zhang, L., Kostenis, E., Felder, C. C., Bymaster, F. P., Brodkin, J., Shannon, H., Xia, B., Duttaroy, A., Deng, C. X. and Wess, J. (2001) Generation and pharmacological analysis of M2 and M4 muscarinic receptor knockout mice. Life Sci, 68: 2457-2466. [PMID:11392613]

22. Gomeza, J., Zhang, L., Kostenis, E., Felder, C., Bymaster, F., Brodkin, J., Shannon, H., Xia, B., Deng, C. and Wess, J. (1999) Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M4 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A., 96: 10483-10488. [PMID:10468635]

23. Grewal, R. P., Martinez, M., Hoehe, M., Bonner, T. I., Gershon, E. S. and Detera-Wadleigh, S. (1992) Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4). Genomics, 13: 239-240. [PMID:1577490]

24. Harvey, A. L., Kornisiuk, E., Bradley, K. N., Cerveñansky, C., Durán, R., Adrover, M., Sánchez, G. and Jerusalinsky, D. (2002) Effects of muscarinic toxins MT1 and MT2 from green mamba on different muscarinic cholinoceptors. Neurochem Res, 27: 1543-1554. [PMID:12512959]

25. Hassall, C. J., Stanford, S. C., Burnstock, G. and Buckley, N. J. (1993) Co-expression of four muscarinic receptor genes by the intrinsic neurons of the rat and guinea-pig heart. Neuroscience, 56: 1041-1048. [PMID:8284034]

26. Hirose, H., Aoki, I., Kimura, T., Fujikawa, T., Numazawa, T., Sasaki, K., Sato, A., Hasegawa, T., Nishikibe, M., Mitsuya, M., Ohtake, N., Mase, T. and Noguchi, K. (2001) Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity. J Pharmacol Exp Ther, 297: 790-797. [PMID:11303071]

27. Hohmann, C. F., Potter, E. D. and Levey, A. I. (1995) Development of muscarinic receptor subtypes in the forebrain of the mouse. J Comp Neurol, 358: 88-101. [PMID:7560279]

28. Huang, F., Buchwald, P., Browne, C. E., Farag, H. H., Wu, W. M., Ji, F., Hochhaus, G. and Bodor, N. (2001) Receptor binding studies of soft anticholinergic agents. AAPS PharmSci, 3: E30-E30. [PMID:12049493]

29. Jakubik, J., Bacakova, L., El-Fakahany, E. E. and Tucek, S. (1997) Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic receptors. Mol. Pharmacol., 52: 172-179. [PMID:9224827]

30. Jolkkonen, M., Van Giersbergen, P. L. M., Hellman, U., Wernstedt, C. and Karlsson, E. (1994) A toxin from the green mamba Dendroaspis angusticeps; amino acid sequence and selectivity for muscarinic m4 receptors. FEBS Lett., 352: 91-94. [PMID:7925952]

31. Kashihara, K., Varga, E. V., Waite, S. L., Roeske, W. R. and Yamamura, H. I. (1992) Cloning of the rat M3, M4 and M5 muscarinic acetylcholine receptor genes by the polymerase chain reaction (PCR) and the pharmacological characterization of the expressed genes. Life Sci, 51: 955-971. [PMID:1325587]

32. Khattar, S. K., Bora, R. S., Priyadarsiny, P., Gupta, D., Khanna, A., Narayanan, K. L., Babu, V., Chugh, A. and Saini, K. S. (2006) High level stable expression of pharmacologically active human M1-M5 muscarinic receptor subtypes in mammalian cells. Biotechnol Lett, 28: 121-129. [PMID:16369696]

33. Lambrecht, G., Moser, U., Grimm, U., Pfaff, O., Hermanni, U., Hildebrandt, C., Waelbroeck, M., Christophe, J. and Mutschler, E. (1993) New functionally selective muscarinic agonists. Life Sci, 52: 481-488. [PMID:7680092]

34. Lazareno, S. and Birdsall, N. J. M. (1993) Pharmacological characterization of acetylcholine-stimulated [35S]-GTPγS binding mediated by human muscarinic m1-m4 receptors, antagonist studies. Br. J. Pharmacol., 109: 1120-1127. [PMID:8401923]

35. Lazareno, S. and Birdsall, N. J. M. (1995) Detection, quantitation and verification of allosteric interactions of agents with labelled and unlabelled ligands at G protein-coupled receptors, interactions of strychnine and acetylcholine at muscarinic receptors. Mol. Pharmacol., 48: 362-378. [PMID:7651370]

36. Lazareno, S., Dolezal, V., Popham, A. and Birdsall, N. J. (2004) Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol Pharmacol, 65: 257-266. [PMID:14722259]

37. Lazareno, S., Farries, T. and Birdsall, N. J. M. (1993) Pharmacological characterization of guanine nucleotide exchange reactions in membranes from CHO cells stably transfected with human muscarinic receptors M1 - M4. Life Sci., 52: 449-456. [PMID:8441327]

38. Lazareno, S., Gharagozloo, P., Kuonen, D., Popham, A. and Birdsall, N. J. M. (1998) Subtype selective positive cooperative interactions between brucine analogues and acetylcholine at muscarinic receptors, radioligand binding studies. Mol. Pharmacol., 53: 573-589. [PMID:9495826]

39. Lazareno, S., Popham, A. and Birdsall, N. J. (2000) Allosteric interactions of staurosporine and other indolocarbazoles with N-[methyl-(3)H]scopolamine and acetylcholine at muscarinic receptor subtypes: identification of a second allosteric site. Mol Pharmacol, 58: 194-207. [PMID:10860942]

40. Lazareno, S., Popham, A. and Birdsall, N. J. (2002) Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors. Mol Pharmacol, 62: 1492-1505. [PMID:12435818]

41. Levey, A. I., Edmunds, S. M., Koliatsos, V., Wiley, R. G. and Heilman, C. J. (1995) Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation. J Neurosci, 15: 4077-4092. [PMID:7751967]

42. Matsui, M., Araki, Y., Karasawa, H., Matsubara, N., Taketo, M. M. and Seldin, M. F. (1999) Mapping of five subtype genes for muscarinic acetylcholine receptor to mouse chromosomes. Genes Genet Syst, 74: 15-21. [PMID:10549128]

43. Matsui, M., Yamada, S., Oki, T., Manabe, T., Taketo, M. M. and Ehlert, F. J. (2004) Functional analysis of muscarinic acetylcholine receptors using knockout mice. Life Sci, 75: 2971-2981. [PMID:15474550]

44. Migeon, J. C., Thomas, S. L. and Nathanson, N. M. (1995) Differential coupling of m2 and m4 muscarinic receptors to inhibition of adenylyl cyclase by Gi alpha and G(o)alpha subunits. J Biol Chem, 270: 16070-16074. [PMID:7608168]

45. Miller, J. H., Aagaard, P. J., Gibson, V. A. and McKinney, M. (1992) Binding and functional selectivity of himbacine for cloned and neuronal muscarinic receptors. J Pharmacol Exp Ther, 263: 663-667. [PMID:1331410]

46. Miller, J. H., Gibson, V. A. and McKinney, M. (1991) Binding of [3H]AF-DX 384 to cloned and native muscarinic receptors. J Pharmacol Exp Ther, 259: 601-607. [PMID:1941609]

47. Oki, T., Takagi, Y., Inagaki, S., Taketo, M. M., Manabe, T., Matsui, M. and Yamada, S. (2005) Quantitative analysis of binding parameters of [3H]N-methylscopolamine in central nervous system of muscarinic acetylcholine receptor knockout mice. Brain Res Mol Brain Res, 133: 6-11. [PMID:15661360]

48. Olianas, M. C., Adem, A., Karlsson, E. and Onali, P. (1996) Rat striatal muscarinic receptors coupled to inhibition of adenylyl cyclase activity, potent block by the selective m4 ligand muscarinic toxin 3 (MT3). Br. J. Pharmacol., 118: 283-288. [PMID:8735628]

49. Olianas, M. C., Ingianni, A., Maullu, C., Adem, A., Karlsson, E. and Onali, P. (1999) Selectivity profile of muscarinic toxin 3 in functional assays of cloned and native receptors. J Pharmacol Exp Ther, 288: 164-170. [PMID:9862767]

50. Onali, P. and Olianas, M. C. (2002) Muscarinic M4 receptor inhibition of dopamine D1-like receptor signalling in rat nucleus accumbens. Eur J Pharmacol, 448: 105-111. [PMID:12144929]

51. Orman, B., Sterin-Borda, L., Reina, S. and Borda, E. S. (2005) Neuronal nitric oxide synthase activity in rat urinary bladder detrusor: participation in M3 and M4 muscarinic receptor function. Auton Autacoid Pharmacol, 25: 93-100. [PMID:15955028]

52. Peralta, E. G., Ashkenazi, A., Winslow, J. W., Ramachandran, J. and Capon, D. J. (1988) Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature, 334: 434-437. [PMID:2841607]

53. Peralta, E. G., Ashkenazi, A., Winslow, J. W., Smith, D. H., Ramachandran, J. and Capon, D. J. (1987) Distinct primary structures, ligand binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J., 6: 3923-3929. [PMID:3443095]

54. Preiksaitis, H. G., Krysiak, P. S., Chrones, T., Rajgopal, V. and Laurier, L. G. (2000) Pharmacological and molecular characterization of muscarinic receptor subtypes in human esophageal smooth muscle. J Pharmacol Exp Ther, 295: 879-888. [PMID:11082420]

55. Richards, M. H. and Van Giersbergen, P. L. (1995) Human muscarinic receptors expressed in A9L and CHO cells, activation by full and partial agonists. Br. J. Pharmacol., 114: 1242-1249. [PMID:7620715]

56. Rosenblum, K., Futter, M., Jones, M., Hulme, E. C. and Bliss, T. V. (2000) ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. J Neurosci, 20: 977-985. [PMID:10648702]

57. Sheffler, DJ; Williams, R; Bridges, TM; Xiang, Z; Kane, AS; Byun, NE; Jadhav, S; Mock, MM; Zheng, F; Lewis, LM; et al.. (2009) A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning. Mol. Pharmacol., 76 (2): 356-68. [PMID:19407080]

58. Stengel, P. W. and Cohen, M. L. (2002) Muscarinic receptor knockout mice: role of muscarinic acetylcholine receptors M(2), M(3), and M(4) in carbamylcholine-induced gallbladder contractility. J Pharmacol Exp Ther, 301: 643-650. [PMID:11961069]

59. Takeuchi, T., Fujinami, K., Goto, H., Fujita, A., Taketo, M. M., Manabe, T., Matsui, M. and Hata, F. (2005) Roles of M2 and M4 muscarinic receptors in regulating acetylcholine release from myenteric neurons of mouse ileum. J Neurophysiol, 93: 2841-2848. [PMID:15574798]

60. Trendelenburg, A. U., Gomeza, J., Klebroff, W., Zhou, H. and Wess, J. (2003) Heterogeneity of presynaptic muscarinic receptors mediating inhibition of sympathetic transmitter release: a study with M2- and M4-receptor-deficient mice. Br J Pharmacol, 138: 469-480. [PMID:12569072]

61. Tseng, J., Erbe, C. B., Kwitek, A. E., Jacob, H. J., Popper, P. and Wackym, P. A. (2002) Radiation hybrid mapping of five muscarinic acetylcholine receptor subtype genes in Rattus norvegicus. Hear Res, 174: 86-92. [PMID:12433399]

62. Tyagi, S., Tyagi, P., Van-le, S., Yoshimura, N., Chancellor, M. B. and de Miguel, F. (2006) Qualitative and quantitative expression profile of muscarinic receptors in human urothelium and detrusor. J Urol, 176: 1673-1678. [PMID:16952712]

63. Tzavara, E. T., Bymaster, F. P., Felder, C. C., Wade, M., Gomeza, J., Wess, J., McKinzie, D. L. and Nomikos, G. G. (2003) Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice. Mol Psychiatry, 8: 673-679. [PMID:12874603]

64. Vilaro, M. T., Palacios, J. M. and Mengod, G. (1994) Multiplicity of muscarinic autoreceptor subtypes? Comparison of the distribution of cholinergic cells and cells containing mRNA for five subtypes of muscarinic receptors in the brain. Brain Res. Mol. Brain Res., 21: 30-46. [PMID:8164520]

65. Wackym, P. A., Chen, C. T., Ishiyama, A., Pettis, R. M., López, I. A. and Hoffman, L. (1996) Muscarinic acetylcholine receptor subtype mRNAs in the human and rat vestibular periphery. Cell Biol Int, 20: 187-192. [PMID:8673067]

66. Waelbroeck, M; De Neef, P; Domenach, V; Vandermeers-Piret, MC; Vandermeers, A. (1996) Binding of the labelled muscarinic toxin 125I-MT1 to rat brain muscarinic M1 receptors. Eur. J. Pharmacol., 305 (1-3): 187-92. [PMID:8813552]

67. Wang, S. Z. and El-Fakahany, E. E. (1993) Application of transfected cell lines in studies of functional receptor subtype selectivity of muscarinic agonists. J Pharmacol Exp Ther, 266: 237-243. [PMID:7687290]

68. Watson, J., Brough, S., Coldwell, M. C., Gager, T., Ho, M., Hunter, A. J., Jerman, J., Middlemiss, D. N., Riley, G. J. and Brown, A. M. (1998) Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br J Pharmacol, 125: 1413-1420. [PMID:9884068]

69. Weiner, D. M., Levey, A. I. and Brann, M. R. (1990) Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia. Proc. Natl. Acad. Sci. U.S.A., 87: 7050-7054. [PMID:2402490]

70. Wess, J. (2003) Novel insights into muscarinic acetylcholine receptor function using gene targeting technology. Trends Pharmacol Sci, 24: 414-420. [PMID:12915051]

71. Wess, J. (2004) Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol, 44: 423-450. [PMID:14744253]

72. Wess, J., Duttaroy, A., Zhang, W., Gomeza, J., Cui, Y., Miyakawa, T., Bymaster, F. P., McKinzie, L., Felder, C. C., Lamping, K. G., Faraci, F. M., Deng, C. and Yamada, M. (2003) M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system. Receptors Channels, 9: 279-290. [PMID:12893539]

73. Wood, I. C., Roopra, A., Harrington, C. and Buckley, N. J. (1995) Structure of the m4 cholinergic muscarinic receptor gene and its promoter. J Biol Chem, 270: 30933-30940. [PMID:8537349]

74. Wood, M. D., Murkitt, K. L., Ho, M., Watson, J. M., Brown, F., Hunter, A. J. and Middlemiss, D. N. (1999) Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry. Br J Pharmacol, 126: 1620-1624. [PMID:10323594]

75. Yasuda, R. P., Ciesla, W., Flores, L. R., Wall, S. J., Li, M., Satkus, S. A., Weisstein, J. S., Spagnola, B. V. and Wolfe, B. B. (1993) Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain. Mol Pharmacol, 43: 149-157. [PMID:8429821]

76. Zhang, W., Basile, A. S., Gomeza, J., Volpicelli, L. A., Levey, A. I. and Wess, J. (2002) Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. J Neurosci, 22: 1709-1717. [PMID:11880500]

77. Zhang, W., Yamada, M., Gomeza, J., Basile, A. S. and Wess, J. (2002) Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice. J Neurosci, 22: 6347-6352. [PMID:12151512]

To cite this database 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): M4 receptor. Last modified on 05/03/2013. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=16.


Contact us | Print | Back to top | Help