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Muskarinski acetilholinski receptor M4
Muskarinski acetilholinski receptor M4
Identifikatori
Simboli	CHRM4; HM4; M4R
Vanjski ID	OMIM: 118495 MGI: 88399 HomoloGene: 20192 IUPHAR: M4 GeneCards: CHRM4 Gene
Ontologija gena
Molekularna funkcija	• receptorska aktivnost; • aktivnost G-protein spregnutog receptora; • aktivnost muskarinskog acetilholinskog receptora; • aktivnost faktor razmene guanil-nukleotida;
Celularna komponenta	• membranska frakcija; • ćelijska membrana; • integralno sa ćelijskom membranom; • postsinaptička gustina; • ćelijska spoj; • asimetrična sinapsa; • sarkolema; • neuronsko ćelijsko telo; • aksonski terminus; • intracelularni deo; • postsinaptička membrana;
Biološki proces	• prenos signala; • signalni put receptora sa ćelijske površine; • inhibicija aktivnosti adenilat ciklaze muskarinskim acetilholinskim receptorima; • signalni put muskarinskog acetilholinskog receptora; • ćelijska proliferacija; • respons na organske supstance;
Ortolozi
Vrsta	Čovek
Entrez	1132
Ensembl	ENSG00000180720
UniProt	P08173
RefSeq (mRNA)	NM_000741
RefSeq (protein)	NP_000732
Lokacija (UCSC)	Chr 11:; 46.41 - 46.41 Mb
PubMed pretraga	[1]

Muskarinski acetilholinski receptor M₄ (muskarinski holinergijski receptor 4, CHRM4), je protein koji je kod ljudi kodiran CHRM4 genom.^[1]^[2]

Funkcije

Muskarinski acetilholinski receptori pripadaju velikoj familiji G protein spregnutih receptora. Funkcionalna raznovrsnost ovih receptora je definisana vezivanjem acetilholina, i obuhvata ćelijske odgovore poput inhibicije adenilat ciklaze, fosfoinozitidne degeneracije i modulacije kalijumovih kanala. Muskarinski receptori posreduju mnoge efekte acetilholina u centralnom i perifernom nervnom sistemu. Klinički značaj ovoj receptora nije poznat; međutim, studije na miševima su ustanovile vezu između njegovog dejstva i inhibicije adenilil ciklaze.^[1]

M₄ muskarinski receptori deluju kao inhibitorni autoreceptori za acetilholin. Aktivacija M₄ receptora inhibira oslobađanje acetilholina u striatumu. M₂ podtip acetilholinksog receptora deluje na sličan način, kao inhibitorni autoreceptor acetilholinskog otpuštanja, mada taj receptor deluje prvenstveno u hipokampusu i cerebralnom korteksu.

Muskarinski acetilholinski receptori imaju regulatorno dejstvo na dopaminergijsku neurotransmisiju. Aktivacija M₄ receptora u striatumu inhibira D₁-indukovanu lokomotornu stimulaciju kod miševa. Miševi koji su deficitarni u M₄ receptorima ispoljavaju povećanu lokomotornu stimulaciju u odgovoru na D₁ agoniste, amfetamin i kokain.^[3]^[4]^[5] Neurotransmisija u striatumu utiče na ekstrapiramidalnu motornu kontrolu, tako da alteracije M₄ aktivnosti mogu da doprinosu oboljenjima poput Parkinsonove bolesti.^[6]^[7]^[8]

Ligandi

===Ortosterni agonisti===

Alosterni agonisti

LY-2033298^[9]
VU-0152100
VU-0152099^[10]

Antagonisti

AFDX-384 (mešoviti M2/M4 antagonist, N-[2-[2-[(dipropilamino)metil]-1-piperidinil]etil]-5,6-dihidro-6-okso-11H-pirido[2,3-b][1,4]benzodiazepin-11-karboksamid
Dicikloverin^[11]
Himbacin
Mamba toksin 3^[12]
PD-102,807 etil estar (3,6a,11,14-tetrahidro-9-metoksi-2-metil-(12H)-izohino[1,2-b]pirolo[3,2-f][1,3]benzoksazin-1-karboksilne kiseline
PD-0298029
Tropikamid - umereno selektivan u odnosu na druge muskarinske podtipove (oko 2-5 puta)^[13]

Reference

^ ^а ^б „Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4”.
^ Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (1992). „Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)”. Genomics. 13 (1): 239—40. PMID 1577490. doi:10.1016/0888-7543(92)90236-L.
^ Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (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. PMC 17915 . PMID 10468635.
^ Jeon J; Dencker D; Wörtwein G; et al. (2010). „A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors”. J. Neurosci. 30 (6): 2396—405. PMC 2824442 . PMID 20147565. doi:10.1523/JNEUROSCI.3843-09.2010.
^ Schmidt L. S.; Thomsen M.; Weikop P.; Dencker D.; Wess J. R.; Woldbye D. P. D.; Wortwein G.; Fink-Jensen A. (2011). „Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice”. Psychopharmacology. 216 (3): 367—378. PMID 21373792. doi:10.1007/s00213-011-2225-4.
^ Langmead CJ, Watson J, Reavill C (2008). „Muscarinic acetylcholine receptors as CNS drug targets”. Pharmacology & Therapeutics. 117 (2): 232—43. PMID 18082893. doi:10.1016/j.pharmthera.2007.09.009.
^ Stein IS, Hell JW (2010). „CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion”. The EMBO Journal. 29 (12): 1943—5. PMC 2892364 . PMID 20551968. doi:10.1038/emboj.2010.105.
^ Guo ML, Mao LM, Wang JQ (2010). „Modulation of M4 muscarinic acetylcholine receptors by interacting proteins”. Neuroscience Bulletin. 26 (6): 469—73. PMC 3139403 . PMID 21113197.
^ Chan WY; McKinzie DL; Bose S; et al. (2008). „Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia”. PNAS. 105 (31): 10978—83. PMC 2495016 . PMID 18678919. doi:10.1073/pnas.0800567105.
^ Brady AE; Jones CK; Bridges TM; et al. (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. PMC 2745822 . PMID 18772318. doi:10.1124/jpet.108.140350.
^ Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (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. PMID 15922057. doi:10.1016/j.bbr.2005.02.019.
^ Muscarinic toxin 3, Dendroaspis angusticeps (Eastern green mamba)
^ Lazareno S, Buckley NJ, Roberts FF (1990). „Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells”. Molecular Pharmacology. 38 (6): 805—15. PMID 2250662.

Literatura

Goyal RK; Underhill, Lisa H.; Goyal, Raj K. (1989). „Muscarinic receptor subtypes. Physiology and clinical implications.”. N. Engl. J. Med. 321 (15): 1022—9. PMID 2674717. doi:10.1056/NEJM198910123211506.
Brann MR; Ellis J; Jørgensen H; et al. (1994). „Muscarinic acetylcholine receptor subtypes: localization and structure/function.”. Prog. Brain Res. 98: 121—7. PMID 8248499. doi:10.1016/S0079-6123(08)62388-2.
Grewal RP; Martinez M; Hoehe M; et al. (1992). „Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4).”. Genomics. 13 (1): 239—40. PMID 1577490. doi:10.1016/0888-7543(92)90236-L.
Detera-Wadleigh SD, Wiesch D, Bonner TI (1989). „An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4).”. Nucleic Acids Res. 17 (15): 6431. PMC 318330 . PMID 2570410. doi:10.1093/nar/17.15.6431.
Ashkenazi A, Ramachandran J, Capon DJ (1989). „Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes.”. Nature. 340 (6229): 146—50. PMID 2739737. doi:10.1038/340146a0.
Bonner TI, Buckley NJ, Young AC, Brann MR (1987). „Identification of a family of muscarinic acetylcholine receptor genes.”. Science. 237 (4814): 527—32. PMID 3037705. doi:10.1126/science.3037705.
Bonner TI, Young AC, Brann MR, Buckley NJ (1990). „Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes.”. Neuron. 1 (5): 403—10. PMID 3272174. doi:10.1016/0896-6273(88)90190-0.
Peralta EG; Ashkenazi A; Winslow JW; et al. (1988). „Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.”. EMBO J. 6 (13): 3923—9. PMC 553870 . PMID 3443095.
van Koppen CJ, Lenz W, Nathanson NM (1993). „Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene.”. Biochim. Biophys. Acta. 1173 (3): 342—4. PMID 7916637.
Haga K; Kameyama K; Haga T; et al. (1996). „Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.”. J. Biol. Chem. 271 (5): 2776—82. PMID 8576254. doi:10.1074/jbc.271.5.2776.
von der Kammer H; Mayhaus M; Albrecht C; et al. (1998). „Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.”. J. Biol. Chem. 273 (23): 14538—44. PMID 9603968. doi:10.1074/jbc.273.23.14538.
Oldenhof J; Vickery R; Anafi M; et al. (1998). „SH3 binding domains in the dopamine D4 receptor.”. Biochemistry. 37 (45): 15726—36. PMID 9843378. doi:10.1021/bi981634.
Sato KZ; Fujii T; Watanabe Y; et al. (1999). „Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines.”. Neurosci. Lett. 266 (1): 17—20. PMID 10336173. doi:10.1016/S0304-3940(99)00259-1.
Dias Neto E; Correa RG; Verjovski-Almeida S; et al. (2000). „Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.”. Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3491—6. PMC 16267 . PMID 10737800. doi:10.1073/pnas.97.7.3491.
Wang H; Han H; Zhang L; et al. (2001). „Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart.”. Mol. Pharmacol. 59 (5): 1029—36. PMID 11306684.
Buchli R; Ndoye A; Arredondo J; et al. (2002). „Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes.”. Mol. Cell. Biochem. 228 (1–2): 57—72. PMID 11855742. doi:10.1023/A:1013368509855.
McClatchy DB; Knudsen CR; Clark BF; et al. (2002). „Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2”. J. Biol. Chem. 277 (32): 29268—74. PMID 12048193. doi:10.1074/jbc.M203081200.
Dean B; McLeod M; Keriakous D; et al. (2003). „Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia”. Mol. Psychiatry. 7 (10): 1083—91. PMID 12476323. doi:10.1038/sj.mp.4001199.

[entrez-1] а ^б „Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4”.

[pmid1577490-2] Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (1992). „Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)”. Genomics. 13 (1): 239—40. PMID 1577490. doi:10.1016/0888-7543(92)90236-L.

[pmid10468635-3] Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (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. PMC 17915 . PMID 10468635.

[pmid20147565-4] Jeon J; Dencker D; Wörtwein G; et al. (2010). „A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors”. J. Neurosci. 30 (6): 2396—405. PMC 2824442 . PMID 20147565. doi:10.1523/JNEUROSCI.3843-09.2010.

[5] Schmidt L. S.; Thomsen M.; Weikop P.; Dencker D.; Wess J. R.; Woldbye D. P. D.; Wortwein G.; Fink-Jensen A. (2011). „Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice”. Psychopharmacology. 216 (3): 367—378. PMID 21373792. doi:10.1007/s00213-011-2225-4.

[pmid18082893-6] Langmead CJ, Watson J, Reavill C (2008). „Muscarinic acetylcholine receptors as CNS drug targets”. Pharmacology & Therapeutics. 117 (2): 232—43. PMID 18082893. doi:10.1016/j.pharmthera.2007.09.009.

[pmid20551968-7] Stein IS, Hell JW (2010). „CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion”. The EMBO Journal. 29 (12): 1943—5. PMC 2892364 . PMID 20551968. doi:10.1038/emboj.2010.105.

[pmid21113197-8] Guo ML, Mao LM, Wang JQ (2010). „Modulation of M4 muscarinic acetylcholine receptors by interacting proteins”. Neuroscience Bulletin. 26 (6): 469—73. PMC 3139403 . PMID 21113197.

[pmid18678919-9] Chan WY; McKinzie DL; Bose S; et al. (2008). „Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia”. PNAS. 105 (31): 10978—83. PMC 2495016 . PMID 18678919. doi:10.1073/pnas.0800567105.

[pmid18772318-10] Brady AE; Jones CK; Bridges TM; et al. (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. PMC 2745822 . PMID 18772318. doi:10.1124/jpet.108.140350.

[pmid15922057-11] Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (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. PMID 15922057. doi:10.1016/j.bbr.2005.02.019.

[12] Muscarinic toxin 3, Dendroaspis angusticeps (Eastern green mamba)

[pmid2250662-13] Lazareno S, Buckley NJ, Roberts FF (1990). „Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells”. Molecular Pharmacology. 38 (6): 805—15. PMID 2250662.

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