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 [1].
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 [2]. 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 [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) 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 [4].
Adenosine A3 receptor survival signaling
is coupled with the phosphorylation of cAMP responsive element binding protein 1
(CREB1) through
AKT(PKB)-dependent pathway [5].
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 [6].
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 [7].
References:
- Headrick JP, Peart J
A3 adenosine receptor-mediated protection of the ischemic heart.
Vascular pharmacology 2005 Apr-May;42(5-6):271-9
- 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
- Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle L, Khalili K
Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells.
Oncogene 2002 Jun 6;21(25):4060-4
- Shi CS, Kehrl JH
PYK2 links G(q)alpha and G(13)alpha signaling to NF-kappa B activation.
The Journal of biological chemistry 2001 Aug 24;276(34):31845-50
- Das S, Tosaki A, Bagchi D, Maulik N, Das DK
Resveratrol-mediated activation of cAMP response element-binding protein through adenosine A3 receptor by Akt-dependent and -independent pathways.
The Journal of pharmacology and experimental therapeutics 2005 Aug;314(2):762-9
- Hammarberg C, Fredholm BB, Schulte G
Adenosine A3 receptor-mediated regulation of p38 and extracellular-regulated kinase ERK1/2 via phosphatidylinositol-3'-kinase.
Biochemical pharmacology 2004 Jan 1;67(1):129-34
- Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Borea PA
A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/Akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in A375 human melanoma cells.
The Journal of biological chemistry 2005 May 20;280(20):19516-26
