Muscarinic acetylcholine receptor M4: Difference between revisions

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{{Wrongtitle|title=Muscarinic acetylcholine receptor M<sub>4</sub>}}
{{DISPLAYTITLE:Muscarinic acetylcholine receptor M<sub>4</sub>}}
{{Infobox_gene}}
<!--Structure PMID 26958838 -->
The '''muscarinic acetylcholine receptor M<sub>4</sub>''', also known as the '''cholinergic receptor, muscarinic 4''' ('''CHRM4'''), is a [[protein]] that, in humans, is encoded by the  ''CHRM4'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1132| accessdate = }}</ref><ref name="pmid1577490">{{cite journal |vauthors=Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S | title = Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) | journal = Genomics | volume = 13 | issue = 1 | pages = 239–40 | date = May 1992 | pmid = 1577490 | doi = 10.1016/0888-7543(92)90236-L | url =  }}</ref>


<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
==Function==
{{PBB_Controls
M<sub>4</sub> [[muscarinic]] receptors are coupled to G<sub>i/o</sub> heterotrimeric proteins.<ref name="Kou Qin">{{cite journal |vauthors=Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nat. Chem. Biol. | volume = 7 | issue = 10 | pages = 740–7 | year = 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
They function as inhibitory [[autoreceptors]] for acetylcholine. Activation of M<sub>4</sub> receptors inhibits [[acetylcholine]] release in the [[striatum]]. The M<sub>2</sub> subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the [[hippocampus]] and [[cerebral cortex]].
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Cholinergic receptor, muscarinic 4
| HGNCid = 1953
| Symbol = CHRM4
| AltSymbols =; HM4
| OMIM = 118495
| ECnumber = 
| Homologene = 20192
| MGIid = 88399
| Function = {{GNF_GO|id=GO:0001584 |text = rhodopsin-like receptor activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004981 |text = muscarinic acetylcholine receptor activity}}
| Component = {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0045211 |text = postsynaptic membrane}}
| Process = {{GNF_GO|id=GO:0007213 |text = acetylcholine receptor signaling, muscarinic pathway}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1132
    | Hs_Ensembl = 
    | Hs_RefseqProtein = NP_000732
    | Hs_RefseqmRNA = NM_000741
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 
    | Hs_GenLoc_start = 
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 12672
    | Mm_Ensembl = ENSMUSG00000040495
    | Mm_RefseqmRNA = NM_007699
    | Mm_RefseqProtein = NP_031725
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 91728088
    | Mm_GenLoc_end = 91729527
    | Mm_Uniprot = Q0VBU3
  }}
}}
The '''muscarinic acetylcholine receptor M<sub>4</sub>''', also known as the '''cholinergic receptor, muscarinic 4''' ('''CHRM4'''), is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1132| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
[[Muscarinic acetylcholine receptors]] possess a regulatory effect on [[dopaminergic]] [[neurotransmission]]. Activation of M<sub>4</sub> receptors in the [[striatum]] inhibit [[D1 receptor|D<sub>1</sub>]]-induced [[hyperactivity|locomotor stimulation]] in [[mice]]. M<sub>4</sub> receptor-deficient mice exhibit increased locomotor simulation in response to [[dopamine agonist|D<sub>1</sub> agonist]]s, [[amphetamine]] and [[cocaine]].<ref name="pmid10468635">{{cite journal |vauthors=Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J | title = Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 18 | pages = 10483–8 | date = August 1999 | pmid = 10468635 | pmc = 17915 | doi = 10.1073/pnas.96.18.10483 | url =  }}</ref><ref name="pmid20147565">{{cite journal |vauthors=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 | title = A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors | journal = J. Neurosci. | volume = 30 | issue = 6 | pages = 2396–405 | date = February 2010 | pmid = 20147565 | pmc = 2824442 | doi = 10.1523/JNEUROSCI.3843-09.2010 | url =  }}</ref><ref>{{cite journal |vauthors=Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A | title = Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice | journal = Psychopharmacology | volume = 216 | issue = 3 | pages = 367–378 | year = 2011 | pmid = 21373792 | pmc =  3899540| doi = 10.1007/s00213-011-2225-4 }}</ref> Neurotransmission in the striatum influences [[extrapyramidal system|extrapyramidal]] [[motor control]], thus alterations in M<sub>4</sub> activity may contribute to conditions such as [[Parkinson's Disease]].<ref name="pmid18082893">{{cite journal |vauthors=Langmead CJ, Watson J, Reavill C | title = Muscarinic acetylcholine receptors as CNS drug targets | journal = Pharmacology & Therapeutics | volume = 117 | issue = 2 | pages = 232–43 | date = February 2008 | pmid = 18082893 | doi = 10.1016/j.pharmthera.2007.09.009 | url =  }}</ref><ref name="pmid20551968">{{cite journal |vauthors=Stein IS, Hell JW | title = CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion | journal = The EMBO Journal | volume = 29 | issue = 12 | pages = 1943–5 | date = June 2010 | pmid = 20551968 | pmc = 2892364 | doi = 10.1038/emboj.2010.105 | url =  }}</ref><ref name="pmid21113197">{{cite journal |vauthors=Guo ML, Mao LM, Wang JQ | title = Modulation of M4 muscarinic acetylcholine receptors by interacting proteins | journal = Neuroscience Bulletin | volume = 26 | issue = 6 | pages = 469–73 | date = December 2010 | pmid = 21113197 | pmc = 3139403 | doi = 10.1007/s12264-010-0933-0 | url =  }}</ref>
{{PBB_Summary
 
| section_title =  
==Ligands==
| summary_text = The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition.<ref name="entrez">{{cite web | title = Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1132| accessdate = }}</ref>
 
}}
===Orthosteric agonists===
* [[acetylcholine]]
* [[carbachol]]
* [[oxotremorine]]
 
[[File:VU-0152100.png|right|172px|thumb|VU-0152100]]
 
===Positive allosteric modulators===
* LY-2033298 <ref name="pmid18678919">{{cite journal |vauthors=Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC | title = Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia | journal = PNAS | volume = 105 | issue = 31 | pages = 10978–83 | year = 2008 | pmid = 18678919 | pmc = 2495016 | doi = 10.1073/pnas.0800567105 | url =  }}</ref>
* [[VU-0152100]] (ML-108) <ref name="pmid18772318">{{cite journal |vauthors=Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW | title = Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats | journal = J. Pharmacol. Exp. Ther. | volume = 327 | issue = 3 | pages = 941–53 | year = 2008 | pmid = 18772318 | pmc = 2745822 | doi = 10.1124/jpet.108.140350 | url =  }}</ref><ref name="pmid22648127">{{cite journal  |vauthors=Dencker D, Weikop P, Sørensen G, etal |title=An allosteric enhancer of M₄ muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine |journal=Psychopharmacology |volume=224 |issue=2 |pages=277–87 |year=2012 |pmid=22648127 |pmc=3914671 |doi=10.1007/s00213-012-2751-8 |url=}}</ref><ref name="pmid24442096">{{cite journal  |vauthors=Byun NE, Grannan M, Bubser M, etal |title=Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100 |journal=Neuropsychopharmacology |volume=39 |issue=7 |pages=1578–93 |year=2014 |pmid=24442096 |doi=10.1038/npp.2014.2 |pmc=4023154}}</ref><ref name="pmid24480931">{{cite journal |vauthors=Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR |title=Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats |journal=Pharmacology |volume=93 |issue=1–2 |pages=57–64 |year=2014 |pmid=24480931 |doi=10.1159/000357682 |url=}}</ref><ref name="pmid24528004">{{cite journal |vauthors=Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z |title=M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses |journal=ACS Chem Neurosci |volume=5 |issue=4 |pages=318–24 |year=2014 |pmid=24528004 |doi=10.1021/cn500003z |pmc=3990947}}</ref><ref name="pmid24074052">{{cite journal |vauthors=Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B |title=Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor |journal=J. Med. Chem. |volume=56 |issue=20 |pages=8196–200 |year=2013 |pmid=24074052 |doi=10.1021/jm401032k |url=}}</ref>
* VU-0152099 <ref name="pmid18772318"/>
 
===Antagonists===
* [[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]]<ref name="pmid15922057">{{cite journal |vauthors=Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK | title = Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies | journal = Behavioural Brain Research | volume = 161 | issue = 2 | pages = 299–305 | date = June 2005 | pmid = 15922057 | doi = 10.1016/j.bbr.2005.02.019 | url =  }}</ref>
* [[Himbacine]]
* [[Mamba toxin 3]]<ref>https://www.uniprot.org/uniprot/P81031</ref>
* [[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)<ref name="pmid2250662">{{cite journal |vauthors=Lazareno S, Buckley NJ, Roberts FF | title = Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells | journal = Molecular Pharmacology | volume = 38 | issue = 6 | pages = 805–15 | date = December 1990 | pmid = 2250662 | doi =  | url =  }}</ref>


==See also==
==See also==
Line 59: Line 38:


==References==
==References==
{{reflist|2}}
{{reflist|35em}}


==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
* {{cite journal | author = Goyal RK | title = Muscarinic receptor subtypes. Physiology and clinical implications | journal = N. Engl. J. Med. | volume = 321 | issue = 15 | pages = 1022–9 | year = 1989 | pmid = 2674717 | doi = 10.1056/NEJM198910123211506 }}
| citations =
* {{cite journal |vauthors=Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV | title = Muscarinic acetylcholine receptor subtypes: localization and structure/function | journal = Prog. Brain Res. | volume = 98 | issue =  | pages = 121–7 | year = 1993 | pmid = 8248499 | doi = 10.1016/S0079-6123(08)62388-2 }}
*{{cite journal | author=Goyal RK |title=Muscarinic receptor subtypes. Physiology and clinical implications. |journal=N. Engl. J. Med. |volume=321 |issue= 15 |pages= 1022-9 |year= 1989 |pmid= 2674717 |doi= }}
* {{cite journal |vauthors=Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S | title = Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4) | journal = Genomics | volume = 13 | issue = 1 | pages = 239–40 | year = 1992 | pmid = 1577490 | doi = 10.1016/0888-7543(92)90236-L }}
*{{cite journal | author=Brann MR, Ellis J, Jørgensen H, ''et al.'' |title=Muscarinic acetylcholine receptor subtypes: localization and structure/function. |journal=Prog. Brain Res. |volume=98 |issue=  |pages= 121-7 |year= 1994 |pmid= 8248499 |doi= }}
* {{cite journal |vauthors=Detera-Wadleigh SD, Wiesch D, Bonner TI | title = An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4). | journal = Nucleic Acids Res. | volume = 17 | issue = 15 | pages = 6431 | year = 1989 | pmid = 2570410 | pmc = 318330 | doi = 10.1093/nar/17.15.6431 }}
*{{cite journal | author=Grewal RP, Martinez M, Hoehe M, ''et al.'' |title=Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4). |journal=Genomics |volume=13 |issue= 1 |pages= 239-40 |year= 1992 |pmid= 1577490 |doi= }}
* {{cite journal |vauthors=Ashkenazi A, Ramachandran J, Capon DJ | title = Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. | journal = Nature | volume = 340 | issue = 6229 | pages = 146–50 | year = 1989 | pmid = 2739737 | doi = 10.1038/340146a0 }}
*{{cite journal | author=Detera-Wadleigh SD, Wiesch D, Bonner TI |title=An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4). |journal=Nucleic Acids Res. |volume=17 |issue= 15 |pages= 6431 |year= 1989 |pmid= 2570410 |doi= }}
* {{cite journal |vauthors=Bonner TI, Buckley NJ, Young AC, Brann MR | title = Identification of a family of muscarinic acetylcholine receptor genes. | journal = Science | volume = 237 | issue = 4814 | pages = 527–32 | year = 1987 | pmid = 3037705 | doi = 10.1126/science.3037705 }}
*{{cite journal | author=Ashkenazi A, Ramachandran J, Capon DJ |title=Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. |journal=Nature |volume=340 |issue= 6229 |pages= 146-50 |year= 1989 |pmid= 2739737 |doi= 10.1038/340146a0 }}
* {{cite journal |vauthors=Bonner TI, Young AC, Brann MR, Buckley NJ | title = Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. | journal = Neuron | volume = 1 | issue = 5 | pages = 403–10 | year = 1990 | pmid = 3272174 | doi = 10.1016/0896-6273(88)90190-0 }}
*{{cite journal | author=Bonner TI, Buckley NJ, Young AC, Brann MR |title=Identification of a family of muscarinic acetylcholine receptor genes. |journal=Science |volume=237 |issue= 4814 |pages= 527-32 |year= 1987 |pmid= 3037705 |doi= }}
* {{cite journal |vauthors=Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ | title = Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. | journal = EMBO J. | volume = 6 | issue = 13 | pages = 3923–9 | year = 1988 | pmid = 3443095 | pmc = 553870 | doi =  }}
*{{cite journal | author=Bonner TI, Young AC, Brann MR, Buckley NJ |title=Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. |journal=Neuron |volume=1 |issue= 5 |pages= 403-10 |year= 1990 |pmid= 3272174 |doi= }}
* {{cite journal |vauthors=van Koppen CJ, Lenz W, Nathanson NM | title = Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene. | journal = Biochim. Biophys. Acta | volume = 1173 | issue = 3 | pages = 342–4 | year = 1993 | pmid = 7916637 | doi = 10.1016/0167-4781(93)90135-z }}
*{{cite journal | author=Peralta EG, Ashkenazi A, Winslow JW, ''et al.'' |title=Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. |journal=EMBO J. |volume=6 |issue= 13 |pages= 3923-9 |year= 1988 |pmid= 3443095 |doi=  }}
* {{cite journal |vauthors=Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H | title = Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C. | journal = J. Biol. Chem. | volume = 271 | issue = 5 | pages = 2776–82 | year = 1996 | pmid = 8576254 | doi = 10.1074/jbc.271.5.2776 }}
*{{cite journal | author=van Koppen CJ, Lenz W, Nathanson NM |title=Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene. |journal=Biochim. Biophys. Acta |volume=1173 |issue= 3 |pages= 342-4 |year= 1993 |pmid= 7916637 |doi= }}
* {{cite journal |vauthors=von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM | title = Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. | journal = J. Biol. Chem. | volume = 273 | issue = 23 | pages = 14538–44 | year = 1998 | pmid = 9603968 | doi = 10.1074/jbc.273.23.14538 }}
*{{cite journal | author=Haga K, Kameyama K, Haga T, ''et al.'' |title=Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C. |journal=J. Biol. Chem. |volume=271 |issue= 5 |pages= 2776-82 |year= 1996 |pmid= 8576254 |doi= }}
* {{cite journal |vauthors=Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH | title = SH3 binding domains in the dopamine D4 receptor. | journal = Biochemistry | volume = 37 | issue = 45 | pages = 15726–36 | year = 1998 | pmid = 9843378 | doi = 10.1021/bi981634+}}
*{{cite journal | author=von der Kammer H, Mayhaus M, Albrecht C, ''et al.'' |title=Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. |journal=J. Biol. Chem. |volume=273 |issue= 23 |pages= 14538-44 |year= 1998 |pmid= 9603968 |doi= }}
* {{cite journal |vauthors=Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K | title = Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. | journal = Neurosci. Lett. | volume = 266 | issue = 1 | pages = 17–20 | year = 1999 | pmid = 10336173 | doi = 10.1016/S0304-3940(99)00259-1 }}
*{{cite journal | author=Oldenhof J, Vickery R, Anafi M, ''et al.'' |title=SH3 binding domains in the dopamine D4 receptor. |journal=Biochemistry |volume=37 |issue= 45 |pages= 15726-36 |year= 1998 |pmid= 9843378 |doi= 10.1021/bi981634+ }}
* {{cite journal |vauthors=Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ | title = Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 7 | pages = 3491–6 | year = 2000 | pmid = 10737800 | pmc = 16267 | doi = 10.1073/pnas.97.7.3491 }}
*{{cite journal | author=Sato KZ, Fujii T, Watanabe Y, ''et al.'' |title=Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. |journal=Neurosci. Lett. |volume=266 |issue= 1 |pages= 17-20 |year= 1999 |pmid= 10336173 |doi= }}
* {{cite journal |vauthors=Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z | title = Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart. | journal = Mol. Pharmacol. | volume = 59 | issue = 5 | pages = 1029–36 | year = 2001 | pmid = 11306684 | doi =  }}
*{{cite journal | author=Dias Neto E, Correa RG, Verjovski-Almeida S, ''et al.'' |title=Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 7 |pages= 3491-6 |year= 2000 |pmid= 10737800 |doi= }}
* {{cite journal |vauthors=Buchli R, Ndoye A, Arredondo J, Webber RJ, Grando SA | title = Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes. | journal = Mol. Cell. Biochem. | volume = 228 | issue = 1–2 | pages = 57–72 | year = 2002 | pmid = 11855742 | doi = 10.1023/A:1013368509855 }}
*{{cite journal | author=Wang H, Han H, Zhang L, ''et al.'' |title=Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart. |journal=Mol. Pharmacol. |volume=59 |issue= 5 |pages= 1029-36 |year= 2001 |pmid= 11306684 |doi=  }}
* {{cite journal |vauthors=McClatchy DB, Knudsen CR, Clark BF, Kahn RA, Hall RA, Levey AI | title = Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2 | journal = J. Biol. Chem. | volume = 277 | issue = 32 | pages = 29268–74 | year = 2002 | pmid = 12048193 | doi = 10.1074/jbc.M203081200 }}
*{{cite journal | author=Buchli R, Ndoye A, Arredondo J, ''et al.'' |title=Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes. |journal=Mol. Cell. Biochem. |volume=228 |issue= 1-2 |pages= 57-72 |year= 2002 |pmid= 11855742 |doi= }}
* {{cite journal |vauthors=Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E | title = Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia | journal = Mol. Psychiatry | volume = 7 | issue = 10 | pages = 1083–91 | year = 2003 | pmid = 12476323 | doi = 10.1038/sj.mp.4001199 }}
*{{cite journal | author=McClatchy DB, Knudsen CR, Clark BF, ''et al.'' |title=Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2. |journal=J. Biol. Chem. |volume=277 |issue= 32 |pages= 29268-74 |year= 2002 |pmid= 12048193 |doi= 10.1074/jbc.M203081200 }}
*{{cite journal | author=Dean B, McLeod M, Keriakous D, ''et al.'' |title=Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. |journal=Mol. Psychiatry |volume=7 |issue= 10 |pages= 1083-91 |year= 2003 |pmid= 12476323 |doi= 10.1038/sj.mp.4001199 }}
}}
{{refend}}
{{refend}}


{{NLM content}}
{{NLM content}}
{{membrane-protein-stub}}
{{G protein-coupled receptors}}
{{G protein-coupled receptors}}
[[Category:G protein coupled receptors]]
{{Muscarinic acetylcholine receptor modulators}}
 
{{DEFAULTSORT:Muscarinic Acetylcholine Receptor M4}}
 
[[Category:G protein-coupled receptors]]
[[Category:Human proteins]]
[[Category:Muscarinic acetylcholine receptors]]

Latest revision as of 18:01, 24 September 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.[1][2]

Function

M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[3]

They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.

Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonists, amphetamine and cocaine.[4][5][6] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's Disease.[7][8][9]

Ligands

Orthosteric agonists

File:VU-0152100.png
VU-0152100

Positive allosteric modulators

Antagonists

  • 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[17]
  • Himbacine
  • Mamba toxin 3[18]
  • 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)[19]

See also

References

  1. ↑ "Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4".
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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. doi:10.1073/pnas.96.18.10483. PMC 17915. PMID 10468635.
  5. ↑ 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. Neurosci. 30 (6): 2396–405. doi:10.1523/JNEUROSCI.3843-09.2010. PMC 2824442. PMID 20147565.
  6. ↑ Schmidt LS, Thomsen M, Weikop P, Dencker D, Wess J, Woldbye DP, Wortwein G, Fink-Jensen A (2011). "Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice". Psychopharmacology. 216 (3): 367–378. doi:10.1007/s00213-011-2225-4. PMC 3899540. PMID 21373792.
  7. ↑ Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacology & Therapeutics. 117 (2): 232–43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893.
  8. ↑ Stein IS, Hell JW (June 2010). "CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion". The EMBO Journal. 29 (12): 1943–5. doi:10.1038/emboj.2010.105. PMC 2892364. PMID 20551968.
  9. ↑ Guo ML, Mao LM, Wang JQ (December 2010). "Modulation of M4 muscarinic acetylcholine receptors by interacting proteins". Neuroscience Bulletin. 26 (6): 469–73. doi:10.1007/s12264-010-0933-0. PMC 3139403. PMID 21113197.
  10. ↑ Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC (2008). "Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia". PNAS. 105 (31): 10978–83. doi:10.1073/pnas.0800567105. PMC 2495016. PMID 18678919.
  11. ↑ 11.0 11.1 Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW (2008). "Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats". J. Pharmacol. Exp. Ther. 327 (3): 941–53. doi:10.1124/jpet.108.140350. PMC 2745822. PMID 18772318.
  12. ↑ Dencker D, Weikop P, Sørensen G, et al. (2012). "An allosteric enhancer of M₄ muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine". Psychopharmacology. 224 (2): 277–87. doi:10.1007/s00213-012-2751-8. PMC 3914671. PMID 22648127.
  13. ↑ Byun NE, Grannan M, Bubser M, et al. (2014). "Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100". Neuropsychopharmacology. 39 (7): 1578–93. doi:10.1038/npp.2014.2. PMC 4023154. PMID 24442096.
  14. ↑ Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR (2014). "Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats". Pharmacology. 93 (1–2): 57–64. doi:10.1159/000357682. PMID 24480931.
  15. ↑ Pancani T, Bolarinwa C, Smith Y, Lindsley CW, Conn PJ, Xiang Z (2014). "M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses". ACS Chem Neurosci. 5 (4): 318–24. doi:10.1021/cn500003z. PMC 3990947. PMID 24528004.
  16. ↑ Huynh T, Valant C, Crosby IT, Sexton PM, Christopoulos A, Capuano B (2013). "Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor". J. Med. Chem. 56 (20): 8196–200. doi:10.1021/jm401032k. PMID 24074052.
  17. ↑ Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (June 2005). "Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies". Behavioural Brain Research. 161 (2): 299–305. doi:10.1016/j.bbr.2005.02.019. PMID 15922057.
  18. ↑ https://www.uniprot.org/uniprot/P81031
  19. ↑ Lazareno S, Buckley NJ, Roberts FF (December 1990). "Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells". Molecular Pharmacology. 38 (6): 805–15. PMID 2250662.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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