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M4 receptor

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Target not currently curated in GtoImmuPdb

Target id: 16

Nomenclature: M4 receptor

Family: Acetylcholine receptors (muscarinic)

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 479 11p11.2 CHRM4 cholinergic receptor muscarinic 4 3,35
Mouse 7 479 2 50.63 cM Chrm4 cholinergic receptor, muscarinic 4 59
Rat 7 478 3q24 Chrm4 cholinergic receptor, muscarinic 4 46,94,108
Previous and Unofficial Names Click here for help
HM3 [75-76] | Chrm-4 | cholinergic receptor, muscarinic 4 | cholinergic receptor
Database Links Click here for help
Specialist databases
GPCRdb acm4_human (Hs), acm4_mouse (Mm)
Other databases
Alphafold P08173 (Hs), P32211 (Mm), P08485 (Rn)
ChEMBL Target CHEMBL1821 (Hs), CHEMBL4572 (Mm), CHEMBL317 (Rn)
DrugBank Target P08173 (Hs)
Ensembl Gene ENSG00000180720 (Hs), ENSMUSG00000040495 (Mm), ENSRNOG00000017556 (Rn)
Entrez Gene 1132 (Hs), 12672 (Mm), 25111 (Rn)
Human Protein Atlas ENSG00000180720 (Hs)
KEGG Gene hsa:1132 (Hs), mmu:12672 (Mm), rno:25111 (Rn)
OMIM 118495 (Hs)
Pharos P08173 (Hs)
RefSeq Nucleotide NM_000741 (Hs), NM_007699 (Mm), NM_031547 (Rn)
RefSeq Protein NP_000732 (Hs), NP_031725 (Mm), NP_113735 (Rn)
UniProtKB P08173 (Hs), P32211 (Mm), P08485 (Rn)
Wikipedia CHRM4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the M4 muscarinic acetylcholine receptor (M4-mT4L) bound to tiotropium.
PDB Id:  5DSG
Ligand:  tiotropium
Resolution:  2.6Å
Species:  Human
References:  92
Natural/Endogenous Ligands Click here for help
acetylcholine

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]iperoxo Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Agonist 10.1 pKd 82
⤷ pKd 10.1 (Kd 8x10-11 M) [82]
[3H]acetylcholine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Agonist 8.2 pKd 52
⤷ pKd 8.2 (Kd 6.3x10-9 M) [52]
pentylthio-TZTP Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.7 pKi 44
⤷ pKi 8.7 [44]
NNC 11-1585 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.6 pKi 17
⤷ pKi 8.6 [17]
NNC 11-1607 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.1 pKi 17
⤷ pKi 8.1 [17]
xanomeline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 7.4 – 7.7 pKi 61,77,102,109
⤷ pKi 7.4 – 7.7 [61,77,102,109]
NNC 11-1314 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.3 pKi 17
⤷ pKi 7.3 [17]
sabcomeline Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.2 pKi 109
⤷ pKi 7.2 [109]
McN-A-343 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.6 – 6.7 pKi 49
⤷ pKi 5.6 – 6.7 [49]
cevimeline Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 6.0 pKi 58
⤷ pKi 6.0 (Ki 1.012x10-6 M) [58]
Description: Displacement of [3H]QNB from cloned receptor.
arecaidine propargyl ester Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.9 pKi 44
⤷ pKi 5.9 [44]
methacholine Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Rn Agonist 5.8 pKi 74,79
⤷ pKi 5.8 (Ki 1.6x10-6 M) [74,79]
arecoline Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.5 pKi 44,73,79
⤷ pKi 5.5 [44,73,79]
milameline Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.5 pKi 109
⤷ pKi 5.5 [109]
oxotremorine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.2 pKi 44,79
⤷ pKi 5.2 [44,79]
oxotremorine-M Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.2 pKi 44
⤷ pKi 5.2 [44]
pilocarpine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 5.2 pKi 44,79
⤷ pKi 5.2 [44,79]
acetylcholine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 4.5 – 5.6 pKi 44,47
⤷ pKi 4.5 – 5.6 [44,47]
methylfurmethide Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.7 pKi 44
⤷ pKi 4.7 [44]
carbachol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 4.3 – 4.9 pKi 44,109
⤷ pKi 4.3 – 4.9 [44,109]
furtrethonium Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.3 pKi 44
⤷ pKi 4.3 [44]
bethanechol Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 4.0 pKi 44,79
⤷ pKi 4.0 [44,79]
(+)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.4 pEC50 27
⤷ pEC50 5.4 [27]
(-)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 4.8 pEC50 27
⤷ pEC50 4.8 [27]
iperoxo Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - - 82
⤷ [82]
View species-specific agonist tables
Agonist Comments
The binding data for McN-A-343 [49] is found on rat striatum.
Please consult references [5,53,79,101] 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 [53] and full agonists [79,101] at the M4 receptor.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]QNB Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.7 – 10.5 pKd 43,75
⤷ pKd 9.7 – 10.5 (Kd 2x10-10 – 3.16x10-11 M) [43,75]
[3H]N-methyl scopolamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.9 – 10.2 pKd 11,43-44,48,51,101
⤷ pKd 9.9 – 10.2 (Kd 1.4x10-10 – 6x10-11 M) [11,43-44,48,51,101]
[3H]AF DX-384 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.7 pKd 12,64,97
⤷ pKd 8.7 [12,64,97]
biperiden Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.6 pKd 2
⤷ pKd 8.6 (Kd 2.4x10-9 M) [2]
otenzepad Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.0 pKd 28
⤷ pKd 7.0 [28]
tiotropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 10.2 – 10.6 pKi 89,91
⤷ pKi 10.2 – 10.6 [89,91]
3-quinuclidinyl-benzilate Small molecule or natural product Hs Antagonist 10.4 pKi 10
⤷ pKi 10.4 (Ki 4x10-11 M) [10]
umeclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 10.3 pKi 81
⤷ pKi 10.3 [81]
propantheline Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 10.2 pKi 42
⤷ pKi 10.2 [42]
aclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 10.0 pKi 91
⤷ pKi 10.0 [91]
oxyphenonium Small molecule or natural product Approved drug Hs Antagonist 9.8 pKi 10
⤷ pKi 9.8 (Ki 1.45x10-10 M) [10]
atropine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 9.7 pKi 46
⤷ pKi 9.7 [46]
glycopyrrolate Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.1 – 10.0 pKi 87,89
⤷ pKi 9.1 – 10.0 [87,89]
AE9C90CB Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.5 pKi 84
⤷ pKi 9.5 [84]
mepenzolic acid Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.4 pKi 10
⤷ pKi 9.4 (Ki 3.6x10-10 M) [10]
scopolamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 9.1 – 9.5 pKi 2,42
⤷ pKi 9.1 – 9.5 [2,42]
revefenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.3 pKi 39
⤷ pKi 9.3 (Ki 5.5x10-10 M) [39]
Description: Determined from a radioligand binding assay using membranes from CHO‐K1 cells expressing the hM4 receptor, and displacement of [3H]NMS tracer.
ipratropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.2 pKi 40
⤷ pKi 9.2 [40]
4-DAMP Small molecule or natural product Click here for species-specific activity table Rn Antagonist 9.1 pKi 46
⤷ pKi 9.1 [46]
atropine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.7 – 9.5 pKi 19,40,42,76
⤷ pKi 8.7 – 9.5 [19,40,42,76]
4-DAMP Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.9 pKi 25
⤷ pKi 8.9 [25]
oxybutynin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.4 – 8.7 pKi 24,84
⤷ pKi 8.4 – 8.7 [24,84]
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Antagonist 8.5 pKi 10
⤷ pKi 8.5 (Ki 3x10-9 M) [10]
silahexocyclium Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.5 pKi 7
⤷ pKi 8.5 [7]
tolterodine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.3 – 8.4 pKi 32,84
⤷ pKi 8.3 – 8.4 [32,84]
UH-AH 37 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 – 8.4 pKi 32,107
⤷ pKi 8.3 – 8.4 [32,107]
hexocyclium Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 pKi 7
⤷ pKi 8.3 [7]
dicyclomine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.3 pKi 10
⤷ pKi 8.3 (Ki 5x10-9 M) [10]
PCS1055 Small molecule or natural product Hs Antagonist 8.2 pKi 19
⤷ pKi 8.2 [19]
himbacine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 – 8.4 pKi 10,25,45,63
⤷ pKi 8.4 (Ki 4x10-9 M) [10]
pKi 7.9 – 8.2 [25,45,63]
amitriptyline Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.1 pKi 85
⤷ pKi 8.1 (Ki 7.2x10-9 M) [85]
AQ-RA 741 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.8 – 8.2 pKi 25,32
⤷ pKi 7.8 – 8.2 [25,32]
tripitramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 pKi 65
⤷ pKi 7.9 [65]
darifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.3 – 8.1 pKi 32,40,84
⤷ pKi 7.3 – 8.1 [32,40,84]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.7 pKi 46
⤷ pKi 7.7 [46]
AFDX384 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.3 – 8.0 pKi 19,25
⤷ pKi 7.3 – 8.0 [19,25]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.0 – 8.1 pKi 10,25,38,42,45,107
⤷ pKi 8.1 (Ki 8x10-9 M) [10]
pKi 7.0 – 7.6 [25,38,42,45,107]
PD 102807 Small molecule or natural product Hs Antagonist 7.4 – 7.6 pKi 19,70
⤷ pKi 7.4 – 7.6 [19,70]
p-F-HHSiD Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.1 – 7.5 pKi 28,42
⤷ pKi 7.1 – 7.5 [28,42]
dosulepin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.2 pKi 85
⤷ pKi 7.2 (Ki 6.1x10-8 M) [85]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.5 – 7.7 pKi 7,28
⤷ pKi 6.5 – 7.7 [7,28]
muscarinic toxin 1 Peptide Click here for species-specific activity table Hs Antagonist 7.1 pKi 36
⤷ pKi 7.1 [36]
hexahydrodifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.1 pKi 7
⤷ pKi 7.1 [7]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 7.1 pKi 46
⤷ pKi 7.1 [46]
methoctramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.6 – 7.5 pKi 7,25,28,38
⤷ pKi 6.6 – 7.5 [7,25,28,38]
tropicamide Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.9 pKi 10
⤷ pKi 6.9 [10]
solifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.8 pKi 84
⤷ pKi 6.8 [84]
(S)-dimetindene Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.5 pKi 9
⤷ pKi 6.5 (Ki 2.951x10-7 M) [9]
Description: Binding to hM4 receptors expressed in CHO cells.
otenzepad Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.5 pKi 46
⤷ pKi 6.5 [46]
guanylpirenzepine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.2 pKi 100
⤷ pKi 6.2 [100]
muscarinic toxin 2 Peptide Click here for species-specific activity table Hs Antagonist 5.9 pKi 36
⤷ pKi 5.9 [36]
VU0255035 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.9 pKi 83
⤷ pKi 5.9 [83]
lithocholylcholine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.3 pKi 14
⤷ pKi 5.3 [14]
muscarinic toxin 7 Peptide Click here for species-specific activity table Hs Antagonist <5.0 pKi 66
⤷ pKi <5.0 [66]
ML381 Small molecule or natural product Click here for species-specific activity table Hs Antagonist >4.5 pKi 31
⤷ pKi >4.5 (Ki <3x10-5 M) [31]
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 [2].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LY2033298 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 4.9 – 5.5 pKB 13,88
⤷ pKB 4.9 – 5.5 [13,88]
KT 5720 Small molecule or natural product Click here for species-specific activity table Hs Neutral 6.4 pKd 55
⤷ pKd 6.4 [55]
WIN 51,708 Small molecule or natural product Click here for species-specific activity table Hs Negative 6.2 pKd 56
⤷ pKd 6.2 [56]
WIN 62,577 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.9 pKd 56
⤷ pKd 5.9 [56]
Gö 7874 Small molecule or natural product Click here for species-specific activity table Hs Neutral 5.7 pKd 55
⤷ pKd 5.7 [55]
alcuronium Small molecule or natural product Click here for species-specific activity table Hs Negative 5.6 pKd 44
⤷ pKd 5.6 [44]
LY2119620 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 5.5 pKd 20
⤷ pKd 5.5 [20]
brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.7 – 6.0 pKd 44,54
⤷ pKd 4.7 – 6.0 [44,54]
staurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Neutral 5.3 pKd 55
⤷ pKd 5.3 [55]
strychnine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 4.8 – 5.0 pKd 44,51
⤷ pKd 4.8 – 5.0 [44,51]
vinburnine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.6 pKd 44
⤷ pKd 4.6 [44]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.5 pKd 54
⤷ pKd 4.5 [54]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.5 pKd 54
⤷ pKd 4.5 [54]
N-chloromethyl-brucine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.4 pKd 54
⤷ pKd 4.4 [54]
vincamine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.2 pKd 44
⤷ pKd 4.2 [44]
thiochrome Small molecule or natural product Click here for species-specific activity table Hs Positive 4.0 pKd 52
⤷ pKd 4.0 [52]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Neutral 3.6 pKd 54
⤷ pKd 3.6 [54]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Positive 3.6 pKd 54
⤷ pKd 3.6 [54]
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Negative 8.7 pKi 45,69
⤷ pKi 8.7 [45,69]
VU0467154 Small molecule or natural product Ligand has a PDB structure Rn Positive 7.8 pEC50 6
⤷ pEC50 7.8 (EC50 1.78x10-8 M) [6]
VU0152100 Small molecule or natural product Rn Positive 6.4 pEC50 4
⤷ pEC50 6.4 (EC50 3.8x10-7 M) [4]
VU0152099 Small molecule or natural product Rn Positive 6.4 pEC50 4
⤷ pEC50 6.4 (EC50 4.03x10-7 M) [4]
VU0467154 Small molecule or natural product Ligand has a PDB structure Hs Positive 6.2 pEC50 6
⤷ pEC50 6.2 (EC50 6.31x10-7 M) [6]
Description: Potentiation of ACh response at human receptor
VU0467154 Small molecule or natural product Ligand has a PDB structure Monkey Positive 6.0 pEC50 6
⤷ pEC50 6.0 (EC50 1x10-6 M) [6]
VU0010010 Small molecule or natural product Hs Positive - - 18
⤷ [18]
View species-specific allosteric modulator tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
References:  62,75
Tissue Distribution Click here for help
Esophageal smooth muscle.
Species:  Human
Technique:  Radioligand binding.
References:  78
Bladder.
Species:  Human
Technique:  RT-PCR.
References:  95
CNS: forebrain.
Species:  Mouse
Technique:  immunocytochemistry.
References:  41
CNS: cerebral cortex, corpus striatum, thalamus, hypothalamus, pons-medulla.
Species:  Mouse
Technique:  Radioligand binding.
References:  67
Heart: intrinsic neurons.
Species:  Rat
Technique:  in situ hybridisation.
References:  37
CNS: basal forebrain, pedunculopontine and laterodorsal tegmental nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  98
CNS: cerebral cortex, hippocampus, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum.
Species:  Rat
Technique:  Immunoprecipitation.
References:  110
CNS: caudate putamen, nucleus accumbens, olfactory tubercle.
Species:  Rat
Technique:  in situ hybridisation.
References:  103
CNS: hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  57
Vestibular system.
Species:  Rat
Technique:  RT-PCR.
References:  99
Expression Datasets Click here for help

Show »

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]

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Functional Assays Click here for help
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:  46
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:  46
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:  62
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:  17
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:  80
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:  29-30
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:  26,68
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:  1,50-53,55-56
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:  1,53
Physiological Functions Click here for help
Autoreceptor: modulation of acetylcholine release.
Species:  Rat
Tissue:  Urinary bladder.
References:  21
Autoreceptor: modulation of acetylcholine release.
Species:  Human
Tissue:  Urinary bladder detrusor muscle.
References:  22
Contraction.
Species:  Rat
Tissue:  Urinary bladder detrusor muscle.
References:  72
Inhibition of dopaminergic (D1 receptor) signalling.
Species:  Rat
Tissue:  Nucleus accumbens.
References:  71
Cell migration.
Species:  Human
Tissue:  Keratinocytes.
References:  16
Physiological Consequences of Altering Gene Expression Click here for help
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:  111
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:  86
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:  93
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:  112
M4 receptor knockout mice exhibit enhanced dopaminergic locomotor activity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  33-34
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:  16
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:  96
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:  15
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:  90
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:  23
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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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 [8,60,104-106].

References

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