Adenozinski A2A receptor

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Adenozinski A2A receptor

Kristalografska struktura adenozinskog A2A receptora (N-terminus = plavo, C-terminus = crveno) u kompleksu sa ZM-241,385 (štapićasti dijagram), bazirana na 3EML koordinatama.
Dostupne strukture
3EML
Identifikatori
SimboliADORA2A; ADORA2; RDC8; hA2AR
Vanjski IDOMIM102776 MGI99402 HomoloGene20166 IUPHAR: A2A GeneCards: ADORA2A Gene
Pregled RNK izražavanja
podaci
Ortolozi
VrstaČovekMiš
Entrez13511540
EnsemblENSG00000128271ENSMUSG00000020178
UniProtP29274Q2NLC1
RefSeq (mRNA)NM_000675NM_009630
RefSeq (protein)NP_000666NP_033760
Lokacija (UCSC)Chr 22:
23.15 - 23.17 Mb
Chr 10:
74.77 - 74.78 Mb
PubMed pretraga[1][2]

Adenozinski A2A receptor (ADORA2A) je adenozinski receptor. On je kodiran humanim ADORA2A genom.[1][2]

Struktura[uredi | uredi kod]

Ovaj protein je član familije G protein-spregnutih receptora koji imaju sedam transmembranskih alfa heliksa. Kristalografska struktura adenozinskog A2A receptora (3EML) pokazuje da je mesto vezivanja liganda distinktno u odnosu na druge GPCR proteine sa određenom strukturom (npr., beta-2 adrenergički receptor i rodopsin).[3]

Heteromeri[uredi | uredi kod]

Dejstva A2A receptora su komplikovana činjenicom da je mnoštvo funkcionalnih heteromera, koji su kombinacije A2A podjedinica i drugih nesrodnih G-protein spregnutih receptora, nađeno u mozgu. To uvećava kompleksnost uloge adenozina u modulaciji neuronske aktivnosti. Heteromeri koji sadrže adenozinski A1/A2A,[4][5] dopaminski D2/A2A[6] iD3/A2A,[7] glutamatni mGluR5/A2A[8] i kanabinoidni CB1/A2A[9] su zapaženi, kao i CB1/A2A/D2 heterotrimeri.[10] Istraživanje funkcionalnog značaja i endogene uloge tih hibridnih receptora je u toku.[11][12][13]

Funkcija[uredi | uredi kod]

Ovaj protein je jedan od nekoliko podtipova adenozinskih receptora. Njegova aktivnost je posredovana G proteinima koji aktiviraju adenilat ciklazu. Ovog proteina ima u izobilju u bazalnoj gangliji, vaskulaturi i krvnim pločicama. On je jedan od glavnih meta kofeina.[14]

Fiziološka uloga[uredi | uredi kod]

Poput A1, A2A receptori učestvuju u regulaciji potrošnje miokardijalnog kiseonika i koronarnog krvnog protoka.

A2A receptor je odgovoran za regulaciju miokardijalnog protoka krvi putem vazodilatacije koronarnih arterija, čime se povećava krvni protok do miokardijuma, mada to može da dovede do hipotenzije. Kao i A1 receptori, ovo dejstvo normalno služi kao zaštitni mehanizam.

A2A receptori su izraženi u mozgu, gde regulišu glutamatno i dopaminsko oslogađanje. On je potencijalna terapeutska meta za lečenje insomnije, bola, depresije, zavisnosti od droge i Parkinsonove bolesti.[15][16][17][18][19][20][21]

Ligandi[uredi | uredi kod]

Brojni selektivni A2A ligandi su razvijeni,[22][23][24][25][26][27][28][29][30][31][32][33] sa nekoliko mogućih terapeutskih primena.[34][35][36][37][38][39] Starija ispitivanja funkcije adenozinskog receptora, i neselektivni antagonisti adenozinskog receptora kao što je aminofilin, su bili usredsređeni na ulogu adenozinskih receptora u funkciji srca. To je rezultovalo u nekoliko kliničkih ispitivanja tih antagonista za lečenje bradikardijskog srčanog zastoja.[40][41][42][43][44][45][46]

Međutim razvoj selektivnijih A2A liganda je doveo do drugih primena. Najznačajniji fokus istraživanja je potencijalna terapeutska uloga A2A antagonista u lečenju Parkinsonove bolesti.[47][48][49][50]

2

Interakcije[uredi | uredi kod]

Za adenozinski A2A receptor je pokazano da interaguje sa dopaminskim receptorom D2.[58]

Reference[uredi | uredi kod]

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  2. Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (September 1991). „Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor”. Genomics 11 (1): 225–7. DOI:10.1016/0888-7543(91)90125-X. PMID 1662665. 
  3. Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, IJzerman AP, Stevens RC (October 2008). „The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist”. Science 322 (5905): 1211–7. DOI:10.1126/science.1164772. PMC 2586971. PMID 18832607. 
  4. Ciruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortés A, Canela EI, López-Giménez JF, Milligan G, Lluis C, Cunha RA, Ferré S, Franco R (February 2006). „Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers”. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 26 (7): 2080–7. DOI:10.1523/JNEUROSCI.3574-05.2006. PMID 16481441. 
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