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Foydalanuvchi:Xatchiman/Dopamin retseptorlari D2

Vikipediya, ochiq ensiklopediya

Andoza:Cs1 configDofamin retseptori D2 , D2R deb ham ataladi. Tarkibida inson tanasidagi DRD2 geni orqali enkodlanadigan oqsil mavjud. Pol Gringard labalatoriyasidagi qator izlanishlardan so'ng dofamin retseptori antipsixologik dorilarni qo'llash uchun eng maqbul qism deb topdi. Bir nechta olimlar guruhi shu jumladan Solomon, X.Snayder va Filip Seaman hozirda dophamin D2 retseptorlarini aniqlash uchun radioyorliqli antipsikotiv moddadan foydalanishgan[1] Ko'plab psixologik dorilar uchun asosiy retseptorlar dophamin D2 xisoblanadi.DRD2 ning murakkab tuzulmasi atipik antipsixot risperidon yordamida aniqlangan.[2][3]

Funksiyasi

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D2 retseptorlari G proteini G<sub id="mwNg">I</sub> subtipi bilan bog'liq bo'lib G proteini bilan bog'liq retseptor adenyliyl siklaz faoliyatini man qiladi[4].

Sichqonlar dentat girusidagi neyronal kaltsiy sensori (NCS-1) tomonidan D2R sirt qobig'ini tartibga solish tadqiqotida qo'llanilgan, sinaptik plastikatsiya va xotira shakllanishida ishtirok etadi[5]. Tatqiqotlar D2Rning prelimbik kotexda qo'rquv haqidagi xotira shakillanishi[6] va nukleus accumbensdagi xotiraning tanish xususiyatidagi potensial ahamiyatini o'rganib chiqdi[7].

Pashshalarda D2 autoretseptoridagi dophamin neyronlari Parkinson kasalligi patologiyasini chaqiruvchi MPP+ toksini tomonidan induksiya qilingan hujayralarni o'limdan himoya qiladi[8].

Dophaminning optimal dozasi yordamida D1R kognitiv barqarorlashuvini ta'minlaydi, insonlardagi kognitiv barqarorlikni D2R saqlab turadi[9][10][11].

Isoformlar

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Ushbu genni alternativ splikt qilinishi turli hildagi izoformalarni enkod qiluvchi uch turdagi transkript holis bo'lishiga olib keladi[12].

Uzun shakldagi D2Lh "kanonik" ketma-ketlikka ega bo'lib postsinaptik retseptor sifatida ishlaydi[13]. Qisqa shakldagi D2Sh pre-sinaptik bo'lib, sinaptik bo'limdagi dopaminedarajasini tartibga soluvchi avtoretseptorlik vazifasini bajaradi, bunday qarama-qashilik dopaminerjik moddaning ishlab chiqish tezligini oshiradi[13].

Aktiv va harakatsiz holatlar

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D2R konfermerlari agonist va antogonist liganti bilan birgalikda ikki hil butunlay aktiv (D2High) va faol bo'lmagan (D2Low) holatlarda ishlaydi.

Risperidon bilan birlashgan D2R ning monomer faol bo'lmagan konformeri haqida birinchi bor 2018 yilda xabar berilgan (PDB ID: 6CM4). Biroq D2Rning agonist bilan bog'liq bo'lgan faol qismi hali mavjud emas va ko'plab tatqiqotlarda homologik modellashtirish tizimi qo'llagan. Faol va faol bo'lmagan G proteini bilan bog'liq retseptorlar o'rtasidagi farq asosan strukturalarning sitoplazmatik qismida va ayniqsa transmembran sohalarida (TM 5 va 6) konformatsion o'zgarishlar shaklida kuzatiladi. Sitoplazma oxirlarida sodir bo'lgan konformaatsiya o'zgarishlari G proteini TM 5 va 6 o'rtasidagi sitoplazma to'plamiga biriktirilishi tufayli sodir bo'ladi[14].

D2Rning faol ligand holati D2Rning faol bo'lmagan antogonist ligand holatiga nisbatan domenga yaxshiroq bog'lanadi. D2R ning TM 5 va 6 ning sitoplazmatik sohalarida ro'y beradigan konformatsion o'zgarishlar ligand bog'lanish sohasiga ta'sir ko'rsatadi. D2R ning faollashuvi domenning ligand bog'lanish sohasi bilan yaxshi kelishuviga sabab bo'ladi.

D2R ning bog'langan ligandlari uchun mos dorini topish ustidagi tatqiqotlar jarayonida D2R ning qanday holatda ekanligi muhim deb ta'kidlashgan. Ma'lumki agonist va antogonist bog'lamlar o'rganilayotganda to'liq faol va faol bo'lmagan holatdagi D2R qo'llanilishi tavsiya qilingan.

D2R ning muvozanatdan chiqishi nerv tizimidagi signal almashinuvini buzilishiga va shizofreniya, avtizmParkinsonizm kasalliglari kelib chiqishiga sabab bo'lishi mumkin [15]. D2Rning muvozanat buzilishi holatini boshqarish uchun angonist va antogonist ligandlarni qo'shimcha D2Rga qo'shish tavsiya qilinadi. Ko'p hollarda D2R ning muvozanat buzilishi genetika sababidan bo'lishi mumkin va shu sababdan terapiya orqalik davolanadi. Hozircha bu kasalliklarga davolash tartibi aniq mavjud emas.

Allosterik va ortostetik qop

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Dopamine 2 ning reseptorida ortosterik bog'lari (OBS) va ikkinchi darajali bog' (SBP) qopchalarini o'zaro bog'liq bo'lshi alosterik farmakologiya talabi hisoblanadi. SB269652 birikmasi D2Rning salbiy allosterik modulatori hisoblanadi[16].

D2Rning oligomerlashtirilishi

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D2R ning dimetrik va yuqori darajadagi oligomerlik shakli mavjud[17]. D2R monomerlari va TM 4 va TM 5 bilan o'zaro bog'lanish hosil qilishini haqida ba'zi eksperimental va molekulyar modellashtirish tajribalar orqalik olingan ma'lumotlari mavjud[18][19].

Genetika

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Allel variantlari:

Ba'zi tadqiqotchilar Taq 1A polimorfizm (rs1800497) ni DRD2 geniga bog'lagan.Biroq, polimorfizm ANKK1 genining 8-eksonida joylashgan[23]. DRD2 TaqIA polimorfizmi Parkinson kasalligida o'zgarishlarning jadal o'sishi va gollusinatsiyalar bilan bog'liqligi xabar qilingan[24][25]. Dopamin retseptor D2 (rs1076560) ning splice ko'rinishi shizofreniyaga chalingan trunkal tardiv diskinesiyasi, ijobiy va salbiy sindromlar ko'rsatkichining pasaygan faktorlari bilan bog'liq deb topilgan[26].

Ligandlar

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Chlorpromazin va haloperidol kabi antipsixotik dorilarning aksariyati dopamin D2 reseptorining antagonistlari hisoblanadi. Ammo ushbu preporadlar faqat "D2 ga mansub oila" reseptorlari uchun nomutanosib hisoblanadi shu sababdan D2, D3, D4, serotonin, histamin kabi boshqa ko'plab reseptorlar uchun qo'llanilishi, yomon ta'sir qilganligi uchun ilmiy tadqiqotlarda qo'llanilmaydiga vositalar sirasiga kiritilgan. Shunga o'xshab, Parkinson kasalligiga qarshi ishlatilinadigan Bromokriptin va kabergolin dopamin agonistlari kamroq selektiv hisoblanadi va ushbu dorilarning aksariyati D2 agonistlari sifatida qo'llanilishiga qaramay, boshqa subtipslarga ham ta'sir qilishi mumkin. Hozirgi kunga kelib ko'plab D2 selektiv ligandlari mavjud va bu son tadqiqotlar davom etgani sayin ko'payishi mumkin.

Agonistlar

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* Bromocriptine – to'lliq agonist

Qisman agonistlar

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Antagonistlar

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* Atypical antipsychotics ( D2 retseptor to'liq agonists, aripiprazole, brexpiprazole, va boshqalardan tashqari)

Allosteriya modulatorlari

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* Homocysteine – negative allosteric modulator[35]

Heterobivalent ligandlar

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  • 1- (6- (((R,S) -7-HidrokS-2-yl) metilamin]heksil) -3- ((S) -1-metilpirrolidin-2-yl) piridinium bromid (qo'shma, D2R agonisti va nAChR antagonisti) [41]

D2/ A2A ligandlari

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  • A2AAR va D2AR qabul qiluvchilarining ikki xil agonistlari ishlab chiqilgan.[42]

Funksional selektiv ligandlar

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Oqsil-proteinlarning oʻzaro taʼsirlari

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Dopamine retseptori D2 EPB41L1,[44] PPP1R9B[45] va NCS-1 ning o'zaro aloqa qilishi[46].

Receptor oligomerlari

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D2 retseptorlari G protini bilan bog'liq boshqa in vivo (tirik hayvonlarda) heterodimerlar retseptorlari shakillanadi va o'z ichiga quidagilarni oladi[47]:

Manbalar

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  1. ↑ "History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia". Journal of the History of the Neurosciences 22 (1): 62–78. 2013. doi:10.1080/0964704X.2012.678199. PMID 23323533. 
  2. ↑ "Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone". Nature 555 (7695): 269–273. March 2018. doi:10.1038/nature25758. PMID 29466326. PMC 5843546. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=5843546. 
  3. ↑ „NIMH » Molecular Secrets Revealed: Antipsychotic Docked in its Receptor“ (en). www.nimh.nih.gov (2018-yil 29-yanvar). Qaraldi: 2018-yil 26-noyabr.
  4. ↑ "Distinct functions of the two isoforms of dopamine D2 receptors". Nature 408 (6809): 199–203. November 2000. doi:10.1038/35041572. PMID 11089973. 
  5. ↑ "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron 63 (5): 643–56. September 2009. doi:10.1016/j.neuron.2009.08.014. PMID 19755107. 
  6. ↑ "Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear". Neurobiology of Learning and Memory 145: 7–17. November 2017. doi:10.1016/j.nlm.2017.08.009. PMID 28842281. 
  7. ↑ "Dopamine D2 receptors in discrimination learning and spine enlargement". Nature 579 (7800): 555–560. March 2020. doi:10.1038/s41586-020-2115-1. PMID 32214250. https://www.nature.com/articles/s41586-020-2115-1. 
  8. ↑ "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture". Journal of Neurochemistry 126 (4): 529–40. August 2013. doi:10.1111/jnc.12228. PMID 23452092. PMC 3737274. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3737274. 
  9. ↑ "Effects of tolcapone and bromocriptine on cognitive stability and flexibility". Psychopharmacology 235 (4): 1295–1305. April 2018. doi:10.1007/s00213-018-4845-4. PMID 29427081. PMC 5869902. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=5869902. 
  10. ↑ "Interactions of Motivation and Cognitive Control". Current Opinion in Behavioral Sciences 19: 83–90. February 2018. doi:10.1016/j.cobeha.2017.11.009. PMID 30035206. PMC 6051692. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=6051692. 
  11. ↑ "Superior cognitive goal maintenance in carriers of genetic markers linked to reduced striatal D2 receptor density (C957T and DRD2/ANKK1-TaqIA)". PLOS ONE 13 (8): e0201837. 2018. doi:10.1371/journal.pone.0201837. PMID 30125286. PMC 6101371. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=6101371. 
  12. ↑ „Entrez Gene: DRD2 dopamine receptor D2“.
  13. ↑ 13,0 13,1 "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacological Reviews 63 (1): 182–217. March 2011. doi:10.1124/pr.110.002642. PMID 21303898. 
  14. ↑ "Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions". Molecular Diversity 19 (2): 321–32. May 2015. doi:10.1007/s11030-015-9569-3. PMID 25652238. 
  15. ↑ "Brain receptors for antipsychotic drugs and dopamine: direct binding assays". Proceedings of the National Academy of Sciences of the United States of America 72 (11): 4376–80. November 1975. doi:10.1073/pnas.72.11.4376. PMID 1060115. PMC 388724. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=388724. 
  16. ↑ "2 receptor". Biochemical Pharmacology 148: 315–328. February 2018. doi:10.1016/j.bcp.2018.01.002. PMID 29325769. PMC 5800995. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=5800995. 
  17. ↑ "Dopamine D2 receptor dimer formation: evidence from ligand binding". The Journal of Biological Chemistry 276 (25): 22621–9. June 2001. doi:10.1074/jbc.M006936200. PMID 11278324. 
  18. ↑ "The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer". The Journal of Biological Chemistry 278 (7): 4385–8. February 2003. doi:10.1074/jbc.C200679200. PMID 12496294. 
  19. ↑ "Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques" (EN). ACS Chemical Neuroscience 7 (2): 185–95. February 2016. doi:10.1021/acschemneuro.5b00271. PMID 26645629. 
  20. ↑ "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Human Molecular Genetics 12 (3): 205–16. February 2003. doi:10.1093/hmg/ddg055. PMID 12554675. 
  21. ↑ "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Human Molecular Genetics 6 (4): 577–82. April 1997. doi:10.1093/hmg/6.4.577. PMID 9097961. 
  22. ↑ "DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 128B (1): 21–3. July 2004. doi:10.1002/ajmg.b.30007. PMID 15211624. 
  23. ↑ "Comment on "Genetically determined differences in learning from errors"". Science 321 (5886): 200; author reply 200. July 2008. doi:10.1126/science.1155372. PMID 18621654. 
  24. ↑ "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD". Neurology 56 (12): 1757–9. June 2001. doi:10.1212/WNL.56.12.1757. PMID 11425949. 
  25. ↑ "Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease". Neuroscience Letters 355 (3): 193–6. January 2004. doi:10.1016/j.neulet.2003.11.006. PMID 14732464. 
  26. ↑ "The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects". Psychiatric Genetics 30 (5): 125–135. 2020. doi:10.1097/YPG.0000000000000258. PMID 32931693. PMC 10111058. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=10111058. 
  27. ↑ „Abilify uchun“. RxList.com (2010-yil 21-yanvar). Qaraldi: 2010-yil 21-yanvar.
  28. ↑ 28,0 28,1 "Dopamine D2High fensiklidinlar, lisergik kislota dietilamid, salvinorin A va modafinil tomonidan qo'zg'atiluvchi retseptorlar". Synapse 63 (8): 698–704. August 2009. doi:10.1002/syn.20647. PMID 19391150. 
  29. ↑ "Selektiv dopamini D2 ning qisman agonistini hisoblanadi, miyaga ta'sir qiluvchi D3 ning kuchli antogonisti hisoblanadi". Bioorganic & Medicinal Chemistry Letters 20 (6): 2013–6. March 2010. doi:10.1016/j.bmcl.2010.01.090. PMID 20153647. 
  30. ↑ "Lysergic acid diethylamide (LSD) dopaminerjik D2 retseptorlarining qisman agonisti bo'lib, vitroda laktotroflarda dopamin vositalaridagi prolaktin sekretsiyasini kuchaytiradi.". Life Sciences 63 (3): 215–22. 1998. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051. 
  31. ↑ "Dopamin D2High retseptorlarida memantin agonist ta'siri". Synapse 62 (2): 149–53. February 2008. doi:10.1002/syn.20472. PMID 18000814. 
  32. ↑ "Demanslardan tashqari psixiatrik kasalliklarni davolashda memantinning roli: hozirgi klinik dalillarni ko'rib chiqish". CNS Drugs 26 (8): 663–90. August 2012. doi:10.2165/11634390-000000000-00000. PMID 22784018. 
  33. ↑ "Neyrofunktsionallik bilan baholangan semirish va giyohvandlik o'rtasidagi o'xshashlik konsepsiyasi.". Journal of Addictive Diseases 23 (3): 39–53. 2004. doi:10.1300/J069v23n03_04. PMID 15256343. 
  34. ↑ "D2 dopamin retseptorlari-selektiv antagonisti bo'lgan SV 293 ning D2 retseptorlari yordamida GIRK kanalini faollashtirishga va adenilil siklaza qarshiligiga ta'siri". Pharmacology 92 (1–2): 84–9. 2013. doi:10.1159/000351971. PMID 23942137. 
  35. ↑ "Allosteric modulation of dopamine D2 receptors by homocysteine". Journal of Proteome Research 5 (11): 3077–83. November 2006. doi:10.1021/pr0601382. PMID 17081059. 
  36. ↑ "PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia". European Neuropsychopharmacology 23 (3): 253–62. March 2013. doi:10.1016/j.euroneuro.2012.04.010. PMID 22658400. 
  37. ↑ "A new mechanism of allostery in a G protein-coupled receptor dimer". Nature Chemical Biology 10 (9): 745–52. September 2014. doi:10.1038/nchembio.1593. PMID 25108820. PMC 4138267. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=4138267. 
  38. ↑ "Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation". European Neuropsychopharmacology 25 (9): 1470–9. September 2015. doi:10.1016/j.euroneuro.2014.09.016. PMID 25453482. 
  39. ↑ "The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors". Molecular Pharmacology 78 (5): 925–34. November 2010. doi:10.1124/mol.110.065755. PMID 20702763. PMC 2981362. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2981362. 
  40. ↑ "3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs". Molecular Pharmacology 91 (6): 586–594. June 2017. doi:10.1124/mol.116.107607. PMID 28265019. PMC 5438131. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=5438131. 
  41. ↑ "Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry 101: 367–83. August 2015. doi:10.1016/j.ejmech.2015.06.039. PMID 26164842. 
  42. ↑ "Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology". Angewandte Chemie 60 (33): 18022–18030. August 2021. doi:10.1002/anie.202101478. PMID 33904641. PMC 8456950. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=8456950. 
  43. ↑ "Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy". Proceedings of the National Academy of Sciences of the United States of America 108 (45): 18488–93. November 2011. doi:10.1073/pnas.1104807108. PMID 22025698. PMC 3215024. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3215024. 
  44. ↑ "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Molecular Pharmacology 62 (3): 507–13. September 2002. doi:10.1124/mol.62.3.507. PMID 12181426. 
  45. ↑ "Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein". The Journal of Biological Chemistry 274 (28): 19894–900. July 1999. doi:10.1074/jbc.274.28.19894. PMID 10391935. 
  46. ↑ "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor". The Journal of Neuroscience 22 (19): 8476–86. October 2002. doi:10.1523/JNEUROSCI.22-19-08476.2002. PMID 12351722. PMC 6757796. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=6757796. 
  47. ↑ "Dopamine receptors – IUPHAR Review 13". British Journal of Pharmacology 172 (1): 1–23. January 2015. doi:10.1111/bph.12906. PMID 25671228. PMC 4280963. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=4280963.  
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