Adenosine A2A receptor signaling
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
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
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 . In turn, PKA-cat (cAMP-dependent)
phosphorylates and stimulates cAMP responsive element binding protein 1
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
Stimulation of Adenosine A2A receptor
prevents cells from the apoptosis via PKA-cat
(cAMP-dependent) activation . 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 .
Stimulation of PKA-cat (cAMP-dependent) enhances nuclear
PKC-zeta activity and cell survival .
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
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) .
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 , .
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) . 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
ERK1/2/ ELK1, member of ETS
oncogene family (ELK1) pathway .
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