Protein-coding gene
Themuscarinic acetylcholine receptor M4 , also known as thecholinergic receptor, muscarinic 4 (CHRM4 ), is aprotein that, in humans, is encoded by theCHRM4 gene .[ 5] [ 6]
M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[ 7]
They function as inhibitoryautoreceptors for acetylcholine. Activation of M4 receptors inhibitsacetylcholine release in thestriatum . The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in thehippocampus andcerebral cortex .
Muscarinic acetylcholine receptors possess a regulatory effect ondopaminergic neurotransmission . Activation of M4 receptors in thestriatum inhibitD1 -inducedlocomotor stimulation inmice . M4 receptor-deficient mice exhibit increased locomotor simulation in response toD1 agonists ,amphetamine andcocaine .[ 8] [ 9] [ 10] extrapyramidal motor control , thus alterations in M4 activity may contribute to conditions such asParkinson's disease .[ 11] [ 12] [ 13]
The M4 muscarinic receptor has been found to be a regulator of erythroidprogenitor cell differentiation. Inhibition of the M4 muscarinic receptor provides therapeutic benefits inmyelodysplastic syndrome andanemia .[ 14] [ 15] [ 16]
Positive allosteric modulators [ edit ] AFDX-384 (mixed M2/M4 antagonist, N-[2-[2-[(Dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide, CAS# 118290-27-0)Dicycloverine [ 31] Diphenhydramine Himbacine Mamba toxin 3[ 32] NBI-1076968 [ 33] PD-102,807 (3,6a,11,14-Tetrahydro-9-methoxy-2-methyl-(12H)-isoquino[1,2-b]pyrrolo[3,2-f][1,3]benzoxazine-1-carboxylic acid ethyl ester, CAS# 23062-91-1)PD-0298029 Tropicamide - moderate selectivity over other muscarinic subtypes (2-5x approx)[ 34] ^a b c GRCh38: Ensembl release 89: ENSG00000180720 –Ensembl , May 2017^a b c GRCm38: Ensembl release 89: ENSMUSG00000040495 –Ensembl , May 2017^ "Human PubMed Reference:" .National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" .National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4" .^ Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (May 1992)."Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)" .Genomics .13 (1):239– 40.doi :10.1016/0888-7543(92)90236-L .PMID 1577490 . ^ Qin K, Dong C, Wu G, Lambert NA (2011)."Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers" .Nat. Chem. Biol .7 (10):740– 7.doi :10.1038/nchembio.642 .PMC 3177959 PMID 21873996 . ^ Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (August 1999)."Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice" .Proceedings of the National Academy of Sciences of the United States of America .96 (18):10483– 8.Bibcode :1999PNAS...9610483G .doi :10.1073/pnas.96.18.10483 PMC 17915 PMID 10468635 . ^ Jeon J, Dencker D, Wörtwein G, Woldbye DP, Cui Y, Davis AA, Levey AI, Schütz G, Sager TN, Mørk A, Li C, Deng CX, Fink-Jensen A, Wess J (February 2010)."A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors" .J. 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This article incorporates text from theUnited States National Library of Medicine , which is in thepublic domain .
mAChRs Tooltip Muscarinic acetylcholine receptors
Agonists Antagonists 3-Quinuclidinyl benzilate 4-DAMP Aclidinium bromide (+formoterol )Abediterol AF-DX 250 AF-DX 384 Ambutonium bromide Anisodamine Anisodine Antihistamines (first-generation) (e.g.,brompheniramine ,buclizine ,captodiame ,chlorphenamine (chlorpheniramine) ,cinnarizine ,clemastine ,cyproheptadine ,dimenhydrinate ,dimetindene ,diphenhydramine ,doxylamine ,meclizine ,mequitazine ,perlapine ,phenindamine ,pheniramine ,phenyltoloxamine ,promethazine ,propiomazine ,triprolidine )AQ-RA 741 Atropine Atropine methonitrate Atypical antipsychotics (e.g.,clozapine ,fluperlapine ,olanzapine (+fluoxetine ),rilapine ,quetiapine ,tenilapine ,zotepine )Benactyzine Benzatropine (benztropine) Benzilone Benzilylcholine mustard Benzydamine Bevonium BIBN 99 Biperiden Bornaprine Camylofin CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 Caramiphen Cimetropium bromide Clidinium bromide Cloperastine CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Desfesoterodine Dexetimide DIBD Dicycloverine (dicyclomine) Dihexyverine Difemerine Diphemanil metilsulfate Ditran Drofenine EA-3167 EA-3443 EA-3580 EA-3834 Emepronium bromide Etanautine Etybenzatropine (ethybenztropine) Fenpiverinium Fentonium bromide Fesoterodine Flavoxate Glycopyrronium bromide (+beclometasone/formoterol ,+indacaterol ,+neostigmine )Hexahydrodifenidol Hexahydrosiladifenidol Hexbutinol Hexocyclium Himbacine HL-031,120 Homatropine Imidafenacin Ipratropium bromide (+salbutamol )Isopropamide J-104,129 Hyoscyamine Mamba toxin 3 Mamba toxin 7 Mazaticol Mebeverine Meladrazine Mepenzolate Methantheline Methoctramine Methylatropine Methylhomatropine Methylscopolamine Metixene Muscarinic toxin 7 N-Ethyl-3-piperidyl benzilate N-Methyl-3-piperidyl benzilate Nefopam Octatropine methylbromide (anisotropine methylbromide) Orphenadrine Otenzepad (AF-DX 116) Otilonium bromide Oxapium iodide Oxitropium bromide Oxybutynin Oxyphencyclimine Oxyphenonium bromide PBID PD-102,807 PD-0298029 Penthienate Pethidine pFHHSiD Phenglutarimide Phenyltoloxamine Pipenzolate bromide Piperidolate Pirenzepine Piroheptine Pizotifen Poldine Pridinol Prifinium bromide Procyclidine Profenamine (ethopropazine) Propantheline bromide Propiverine Quinidine 3-Quinuclidinyl thiochromane-4-carboxylate Revefenacin Rociverine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine (hyoscine) Scopolamine butylbromide (hyoscine butylbromide) Silahexacyclium Sofpironium bromide Solifenacin SSRIs Tooltip Selective serotonin reuptake inhibitors (e.g.,femoxetine ,paroxetine )Telenzepine Terodiline Tetracyclic antidepressants (e.g.,amoxapine ,maprotiline ,mianserin ,mirtazapine )Tiemonium iodide Timepidium bromide Tiotropium bromide Tiquizium bromide Tofenacin Tolterodine Tricyclic antidepressants (e.g.,amitriptyline (+perphenazine ),amitriptylinoxide ,butriptyline ,cidoxepin ,clomipramine ,desipramine ,desmethyldesipramine ,dibenzepin ,dosulepin (dothiepin) ,doxepin ,imipramine ,lofepramine ,nitroxazepine ,northiaden (desmethyldosulepin) ,nortriptyline ,protriptyline ,quinupramine ,trimipramine )Tridihexethyl Trihexyphenidyl Trimebutine Tripitamine (tripitramine) Tropacine Tropatepine Tropicamide Trospium chloride Typical antipsychotics (e.g.,chlorpromazine ,chlorprothixene ,cyamemazine (cyamepromazine) ,loxapine ,mesoridazine ,thioridazine )Umeclidinium bromide (+vilanterol )WIN-2299 Xanomeline Zamifenacin
Precursors (andprodrugs )
