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