PKA-cat (cAMP-dependent), PtdIns(3,4,5)P3, PDK (PDPK1), STAT3, Adenylate cyclase type I, GSK3 beta, Ca('2+) endoplasmic reticulum lumen, c-Myc, NF-kB, None, DAG, G-protein alpha-i family, G-protein beta/gamma, PLC-beta, G-protein alpha-q/11, c-Raf-1, SOS, RASGRF1, H-Ras, ERK1 (MAPK3), Adenosine A3 receptor, Elk-1, PKC-epsilon, AKT(PKB), 22.214.171.124, IKK (cat), 126.96.36.199, MEK1(MAP2K1), PtdIns(4,5)P2, Shc, PI3K cat class IB (p110-gamma), PI3K reg class IB (p101), CREB1, Pyk2(FAK2), cAMP, Beta-catenin, Cyclin D1, IKK-alpha, IP3, Ca('2+) cytosol, GRB2, IP3 receptor, ATP cytoplasm, PKA-reg (cAMP-dependent), Adenosine extracellular region, TCF7L2 (TCF4), 188.8.131.52, I-kB, MEK2(MAP2K2)
Adenosine A3 receptor signaling
Adenosine is a potent biological mediator that affects numerous cell 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 second messenger pathways such as modulation of cAMP production or the phospholipase C pathway.
Adenosine A3 receptor signaling pathways include activation of G-protein alpha-i family and G-protein alpha-q/11 .
Adenosine A3 receptors interact with the trimeric G-protein alpha/beta/gamma and stimulate the exchange of GDP to GTP bound to G-protein alpha subunits and the dissociation of the beta/gamma heterodimers.
G-protein alpha-i family inhibits activity of Adenylate cyclase 1 ( Adenylate cyclase type I ), thereby decreasing the level of cAMP and the activity of Protein kinase, cAMP-dependent, catalytic ( PKA-cat (cAMP-dependent) ) in cell . PKA-cat (cAMP-dependent) controls Glycogen synthase kinase 3 beta ( GSK3 beta ) activity, a key component of the Wnt signaling pathway. PKA-cat (cAMP-dependent) phosphorylates and inactivates GSK3 beta. Upon activation of Adenosine A3 receptor, non-phosphorylated GSK3 beta phosphorylates and inhibits Catenin (cadherin-associated protein), beta 1, 88kDa ( Beta-catenin ). Consequently, these events lead to the inhibition of cell cycle progression by decreasing Cyclin D1 - and v-myc myelocytomatosis viral oncogene homolog ( c-Myc) transcription .
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 ) and diacylglycerol ( DAG ). The IP3 is released into the cytoplasm and mobilizes Ca('2+) from internal stores, whereas DAG activates Protein kinase C epsilon ( PKC-epsilon ). PKC-epsilon induces PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) ) activation. Pyk2(FAK2) activates V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) through a PI3K -dependent pathway. Pyk2(FAK2) phosphorylates SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ) and stimulates protein cascade Growth factor receptor-bound protein 2 ( GRB2 )/ Son of sevenless homolog ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ). H-Ras interacts with the Phosphoinositide-3-kinase, catalytic, gamma polypeptide ( PI3K cat class IB (p110-gamma) ) leading to an increase in its enzymatic activity and catalysis of phosphorylation of PtdIns(4,5)P2 to form phosphoinositide 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ). A signaling pathway initiated by the receptor via G-protein alpha-q/11 and AKT(PKB) activation leads to the stimulation of Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ). IKK-alpha phosphorylate Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor ( I-kB ) resulting in dissociation of I-kB from Nuclear factor of kappa light polypeptide gene enhancer in B-cells ( NF-kB ) and NF-kB -dependent transcription .
Adenosine A3 receptor survival signaling is coupled with the phosphorylation of cAMP responsive element binding protein 1 ( CREB1 ) through AKT(PKB) -dependent pathway .
The Adenosine A3 receptor signaling pathway involves G-protein beta/gamma activation upon it dissociation from G-protein alpha-i family. G-protein beta/gamma activates PI3K cat class IB (p110-gamma) and induces Mitogen-activated protein kinase 1-3 ( ERK1/2 ) phosphorylation and Signal transducer and activator of transcription 3 ( STAT3 ) activation via PtdIns(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 .
Stimulation of Adenosine A3 receptor in some cell types results in PI3K- dependent phosphorylation of AKT(PKB) and reduction of basal level phosphorylation of ERK1/2 via v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ) inhibition, which in turn inhibits cell proliferation .