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Development A3 receptor signaling

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Development A3 receptor signaling

Adenosine A3 receptor signaling

Adenosine is a potent biological mediator that affects numerouscell types including neural cells, platelets, neutrophils and smooth muscle cells.Currently, four adenosine receptor subtypes have been identified: A1, A2A, A2B and A3.Adenosine receptors are G-protein-coupled receptors that regulate classical secondmessenger pathways such as modulation of cAMP production or the phospholipase Cpathway.

Adenosine A3 receptor signaling pathways include activation ofG-protein alpha-i family and G-protein alpha-q/11 [1].

Adenosine A3 receptors interact with the trimeric G-proteinalpha/beta/gamma and stimulate the exchange of GDP to GTP bound to G-proteinalpha subunits and the dissociation of the beta/gamma heterodimers.

G-protein alpha-i family inhibits activity of Adenylate cyclase1 ( Adenylate cyclase type I ), thereby decreasing the level of cAMP andthe activity of Protein kinase, cAMP-dependent, catalytic ( PKA-cat(cAMP-dependent) ) in cell [2]. PKA-cat (cAMP-dependent) controlsGlycogen synthase kinase 3 beta ( GSK3 beta ) activity, a key component of the Wntsignaling pathway. PKA-cat (cAMP-dependent) phosphorylates and inactivates GSK3beta. Upon activation of Adenosine A3 receptor, non-phosphorylated GSK3beta phosphorylates and inhibits Catenin (cadherin-associated protein), beta 1, 88kDa( Beta-catenin ). Consequently, these events lead to the inhibition of cell cycleprogression by decreasing Cyclin D1 - and v-myc myelocytomatosis viral oncogenehomolog ( c-Myc) transcription [3].

G-protein alpha-q/11 activates Phospholipase C beta (PLC-beta ), which catalyzes hydrolysis of phosphoinositide 4,5-bisphosphate (PtdIns(4,5)P2 ) to form inositol 1,4,5-triphosphate ( IP3 ) anddiacylglycerol ( DAG ). The IP3 is released into the cytoplasm andmobilizes Ca('2+) from internal stores, whereas DAG activates Proteinkinase C epsilon ( PKC-epsilon ). PKC-epsilon induces PTK2B proteintyrosine kinase 2 beta ( Pyk2(FAK2) ) activation. Pyk2(FAK2) activatesV-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) through a PI3K-dependent pathway. Pyk2(FAK2) phosphorylates SHC (Src homology 2 domaincontaining) transforming protein 1 ( Shc ) and stimulates protein cascade Growthfactor receptor-bound protein 2 ( GRB2 )/ Son of sevenless homolog ( SOS )/v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ). H-Rasinteracts with the Phosphoinositide-3-kinase, catalytic, gamma polypeptide ( PI3K catclass IB (p110-gamma) ) leading to an increase in its enzymatic activity andcatalysis of phosphorylation of PtdIns(4,5)P2 to form phosphoinositide3,4,5-triphosphate ( PtdIns(3,4,5)P3 ). A signaling pathway initiated by thereceptor via G-protein alpha-q/11 and AKT(PKB) activation leads to thestimulation of Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ).IKK-alpha phosphorylate Nuclear factor of kappa light polypeptide gene enhancer inB-cells inhibitor ( I-kB ) resulting in dissociation of I-kB from Nuclearfactor of kappa light polypeptide gene enhancer in B-cells ( NF-kB ) andNF-kB -dependent transcription [4].

Adenosine A3 receptor survival signaling is coupled with thephosphorylation of cAMP responsive element binding protein 1 ( CREB1 ) throughAKT(PKB) -dependent pathway [5].

The Adenosine A3 receptor signaling pathway involvesG-protein beta/gamma activation upon it dissociation from G-protein alpha-ifamily. G-protein beta/gamma activates PI3K cat class IB (p110-gamma)and induces Mitogen-activated protein kinase 1-3 ( ERK1/2 ) phosphorylation andSignal transducer and activator of transcription 3 ( STAT3 ) activation viaPtdIns(3,4,5)P3/ Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1 )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) )pathway [6].

Stimulation of Adenosine A3 receptor in some cell types resultsin PI3K- dependent phosphorylation of AKT(PKB) and reduction of basal levelphosphorylation of ERK1/2 via v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 ) inhibition, which in turn inhibits cell proliferation [7].