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Development A2A receptor signaling

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Development A2A receptor signaling

Adenosine A2A receptor signaling

Adenosine is a potent biological mediator that affects numerouscell types, including neuronal cells, platelets, neutrophils and smooth muscle cells.Currently, four adenosine receptor subtypes have been identified: A1, A2A, A2B and A3.Adenosine receptors belong to the G-protein-coupled receptor family of cell surfacereceptors. Adenosine A2A receptor is G-protein alpha-s coupled receptorthat induces classical second messenger pathway such as modulation of cAMPproduction.

Adenosine A2A receptor interaction with the trimeric G-proteinalpha-s/ beta/gamma causes the exchange of GDP to GTP bound to G protein alphasubunits and the dissociation of the beta/gamma heterodimers.

Activated G-protein alpha-s stimulates Adenylate cyclase 6 ( Adenylatecyclase type VI ) . Adenylate cyclase type VI increases level of cAMPin cells and activate Protein kinase, cAMP-dependent, regulatory ( PKA-reg(cAMP-dependent) ) that results in Protein kinase, cAMP-dependent, catalytic (PKA-cat (cAMP-dependent) ) activation [1]. In turn, PKA-cat(cAMP-dependent) phosphorylates and stimulates cAMP responsive element bindingprotein 1 ( CREB1 ) [2].

Adenosine A2A receptor facilitates protein secretion through theactivation of PKA-cat (cAMP-dependent) and Phosphoinositide-3-kinase, catalytic (PI3K cat class IA ). Activation of Adenosine A2A receptor transientlyincreases the phosphorylation of Mitogen-activated protein kinase 14 ( P38 MAPK )and Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ), V-akt murine thymomaviral oncogene homolog 1 ( AKT(PKB) ), and Activating transcription factor 2 (ATF-2 ) [3].

Stimulation of Adenosine A2A receptor prevents cells from theapoptosis via PKA-cat (cAMP-dependent) activation [4]. PKA-cat(cAMP-dependent) phosphorylates and activates Rho guanine nucleotide exchange factor(GEF) 7 ( BETA-PIX ) that, in turn, activates Ras-related C3 botulinum toxinsubstrate 1 ( Rac1 ) and Cell division cycle 42 ( Cdc42 ). An effector ofCdc42, Par-6 partitioning defective 6 homolog ( PRAD6 ) interacts withCdc42 in a GTP-dependent manner, and also directly binds to Protein kinase C, zeta( PKC-zeta ), forming a stable ternary complex with Cdc42 andPKC-zeta. This association results in stimulation of PKC-zeta kinaseactivity. PKC-zeta prevents apoptosis via phosphorylation of Ribosomal protein S6kinase, 90kDa ( p90Rsk ), which inhibits BCL2-associated agonist of cell death (BAD ) protein [5]. Stimulation of PKA-cat (cAMP-dependent)enhances nuclear PKC-zeta activity and cell survival [6].

Activation of Cdc42 increases the phosphorylation of P38MAPK and JNK(MAPK8-10) as well as that of ATF-2 and Jun oncogene (c-Jun ) via stimulation Mitogen-activated protein kinase kinase kinase 4 (MEKK4(MAP3K4) )/ Mitogen-activated protein kinase kinase 6 MEK6(MAP2K6)/ P38MAPK and p21 protein (Cdc42/Rac)-activated kinase 1 ( PAK1 )/Mitogen-activated protein kinase kinase kinase 1 ( MEKK1 )/ Mitogen-activatedprotein kinase kinase 7( MEK7(MAP2K7)/ JNK(MAPK8-10) pathways [7].

Activated by cAMP guanine nucleotide exchange factor Rap guaninenucleotide exchange factor (GEF) 2 ( PDZ-GEF1 ) stimulates PI3K cat classIA activation via v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras). PI3K cat class IA converts ( PtdIns(4,5)P2 ) to phosphatidylinositol3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) [8].

PtdIns(3,4,5)P3 is a second messenger that directly binds viapleckstrin homology (PH) domen with V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB) ), that activates Conserved helix-loop-helix ubiquitous kinase (IKK-alpha )/ Nuclear factor of kappa light polypeptide gene enhancer in B-cellsinhibitor ( I-kB )/ Nuclear factor of kappa light polypeptide gene enhancer inB-cells ( NF-kB ) signaling [9], [10].

Activation of Adenosine A2a receptor stimulates nitric oxide production inhuman fetal umbilical vein endothelial cells via stimulation of Mitogen-activated proteinkinase 1-3 ( ERK1/2 ) [11]. cAMP binding to Rap guaninenucleotide exchange factor (GEF) 3 ( cAMP-GEFI ) activates transcription of Nitricoxide synthase 3 ( eNOS ) via RAP1A, member of RAS oncogene family ( RAP-1A)/ v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf )/ Mitogen-activatedprotein kinase kinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) )/ ERK1/2/ELK1, member of ETS oncogene family ( ELK1 ) pathway [12].