Adenosine is a potent biological mediator that affects numerous cell 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 surface receptors. Adenosine A2A receptor is G-protein alpha-s coupled receptor that induces classical second messenger pathway such as modulation of cAMP production.

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

Activated G-protein alpha-s stimulates Adenylate cyclase 6 (Adenylate cyclase type VI). Adenylate cyclase type VI increases level of cAMP in 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 binding protein 1 (CREB1) [2].

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

Stimulation of Adenosine A2A receptor prevents cells from the apoptosis 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 toxin substrate 1 (Rac1) and Cell division cycle 42 (Cdc42). An effector of Cdc42, Par-6 partitioning defective 6 homolog (PRAD6) interacts with Cdc42 in a GTP-dependent manner, and also directly binds to Protein kinase C, zeta (PKC-zeta), forming a stable ternary complex with Cdc42 and PKC-zeta. This association results in stimulation of PKC-zeta kinase activity. PKC-zeta prevents apoptosis via phosphorylation of Ribosomal protein S6 kinase, 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 P38 MAPK 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)/ P38 MAPK and p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1)/ Mitogen-activated protein kinase kinase 7(MEK7(MAP2K7)/ JNK(MAPK8-10) pathways [7].

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

PtdIns(3,4,5)P3 is a second messenger that directly binds via pleckstrin 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-cells inhibitor (I-kB)/ Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB) signaling [9], [10].

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

1. Defer N, Best-Belpomme M, Hanoune J
   Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
2. Don J, Stelzer G
   The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis. Molecular and cellular endocrinology 2002 Feb 22;187(1-2):115-24
3. Mori Y, Higuchi M, Masuyama N, Gotoh Y
   Adenosine A2A receptor facilitates calcium-dependent protein secretion through the activation of protein kinase A and phosphatidylinositol-3 kinase in PC12 cells. Cell structure and function 2004 Dec;29(4):101-10
4. Huang NK, Lin YW, Huang CL, Messing RO, Chern Y
   Activation of protein kinase A and atypical protein kinase C by A(2A) adenosine receptors antagonizes apoptosis due to serum deprivation in PC12 cells. The Journal of biological chemistry 2001 Apr 27;276(17):13838-46
5. Hurbin A, Coll JL, Dubrez-Daloz L, Mari B, Auberger P, Brambilla C, Favrot MC
   Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells. The Journal of biological chemistry 2005 May 20;280(20):19757-67
6. Qiu RG, Abo A, Steven Martin G
   A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation. Current biology : CB 2000 Jun 15;10(12):697-707
7. Feoktistov I, Goldstein AE, Biaggioni I
   Cyclic AMP and protein kinase A stimulate Cdc42: role of A(2) adenosine receptors in human mast cells. Molecular pharmacology 2000 Nov;58(5):903-10
8. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
   Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
9. Igarashi J, Michel T
   Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways. The Journal of biological chemistry 2001 Sep 28;276(39):36281-8
10. Carini R, Grazia De Cesaris M, Splendore R, Baldanzi G, Nitti MP, Alchera E, Filigheddu N, Domenicotti C, Pronzato MA, Graziani A, Albano E
    Role of phosphatidylinositol 3-kinase in the development of hepatocyte preconditioning. Gastroenterology 2004 Sep;127(3):914-23
11. Wyatt AW, Steinert JR, Wheeler-Jones CP, Morgan AJ, Sugden D, Pearson JD, Sobrevia L, Mann GE
    Early activation of the p42/p44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Oct;16(12):1584-94
12. Fujita T, Meguro T, Fukuyama R, Nakamuta H, Koida M
    New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells. Checkpoint of modulation by cyclic AMP. The Journal of biological chemistry 2002 Jun 21;277(25):22191-200