Muskarinski acetilholinski receptor M4

Из Википедије, слободне енциклопедије
Muskarinski acetilholinski receptor M4
Identifikatori
Simboli CHRM4; HM4; M4R
Vanjski ID OMIM118495 MGI88399 HomoloGene20192 IUPHAR: M4 GeneCards: CHRM4 Gene
Ortolozi
Vrsta Čovek Miš
Entrez 1132 12672
Ensembl ENSG00000180720 ENSMUSG00000040495
UniProt P08173 Q0VBU3
RefSeq (mRNA) NM_000741 NM_007699.2
RefSeq (protein) NP_000732 NP_031725.1
Lokacija (UCSC) Chr 11:
46.41 - 46.41 Mb
Chr 2:
91.76 - 91.77 Mb
PubMed pretraga [1] [2]

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

Funkcije[уреди]

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[уреди]

===Ortosterni agonisti===

Alosterni agonisti

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[уреди]

  1. 1,0 1,1 „Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4”. 
  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. doi:10.1016/0888-7543(92)90236-L. PMID 1577490. 
  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 17915слободно за читање. PMID 10468635. 
  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. doi:10.1523/JNEUROSCI.3843-09.2010. PMC 2824442слободно за читање. PMID 20147565. 
  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. doi:10.1007/s00213-011-2225-4. PMID 21373792. 
  6. Langmead CJ, Watson J, Reavill C (2008). „Muscarinic acetylcholine receptors as CNS drug targets”. Pharmacology & Therapeutics. 117 (2): 232—43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893. 
  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. doi:10.1038/emboj.2010.105. PMC 2892364слободно за читање. PMID 20551968. 
  8. Guo ML, Mao LM, Wang JQ (2010). „Modulation of M4 muscarinic acetylcholine receptors by interacting proteins”. Neuroscience Bulletin. 26 (6): 469—73. PMC 3139403слободно за читање. PMID 21113197. 
  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. doi:10.1073/pnas.0800567105. PMC 2495016слободно за читање. PMID 18678919. 
  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. doi:10.1124/jpet.108.140350. PMC 2745822слободно за читање. PMID 18772318. 
  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. doi:10.1016/j.bbr.2005.02.019. PMID 15922057. 
  12. Muscarinic toxin 3, Dendroaspis angusticeps (Eastern green mamba)
  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. 

Literatura[уреди]

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  • Grewal RP, Martinez M, Hoehe M; et al. (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. 
  • 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. doi:10.1093/nar/17.15.6431. PMC 318330слободно за читање. PMID 2570410. 
  • 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. doi:10.1038/340146a0. PMID 2739737. 
  • Bonner TI, Buckley NJ, Young AC, Brann MR (1987). „Identification of a family of muscarinic acetylcholine receptor genes.”. Science. 237 (4814): 527—32. doi:10.1126/science.3037705. PMID 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. doi:10.1016/0896-6273(88)90190-0. PMID 3272174. 
  • 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 553870слободно за читање. 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. doi:10.1074/jbc.271.5.2776. PMID 8576254. 
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  • Oldenhof J, Vickery R, Anafi M; et al. (1998). „SH3 binding domains in the dopamine D4 receptor.”. Biochemistry. 37 (45): 15726—36. doi:10.1021/bi981634. PMID 9843378. 
  • 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. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173. 
  • 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. doi:10.1073/pnas.97.7.3491. PMC 16267слободно за читање. PMID 10737800. 
  • 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. doi:10.1023/A:1013368509855. PMID 11855742. 
  • 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. doi:10.1074/jbc.M203081200. PMID 12048193. 
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