Development - A2B receptor: action via G-protein alpha s

Adenosine A2B receptor signaling

Adenosine A2B receptor influences cell differentiation and proliferation. A2B receptors are G-protein-coupled receptors coupling to classical second messenger pathways, such as modulation of Cyclic Adenosine 3',5'-phosphate (cAMP) production or the Phospholipase C (PLC) pathway.

Adenosine A2B receptor interacts with trimeric G-protein alpha-s/G-protein beta/gamma and G-protein alpha-q/G-protein beta/gamma. This causes exchange of GDP for GTP bound to G protein alpha subunits and subsequent dissociation of G-protein beta/gamma heterodimers.

G-protein alpha-s activates Adenylate cyclase I, which then increases levels of cAMP in the cell and activates Protein kinase cAMP-dependent (PKA) inactive complex that results in the activation of PKA [1]. In turn, PKA phosphorylates and inactivates Glycogen synthase kinase 3 beta (GSK3 beta), which leads to attenuation of Beta-catenin inhibition. Consequently, this signaling cascade activates cell cycle progression, initiating activity of Transcription factor 7-like 2 (TCF7L2 (TCF4)) that promotes the expression of Cyclin D1 and V-myc myelocytomatosis viral oncogene homolog (c-Myc) [2]. Phosphorylation and activation of cAMP responsive element binding protein 1 (CREB1) is mainly mediated via adenosine Adenosine A2B receptor [3].

Adenosine stimulates Interleukin 6 (IL-6) expression in human astrocytoma cell lines via Adenosine A2B receptor inducing p38 mitogen-activated protein kinases (p38MAPK). G-protein alpha-q/11 activates Phospholipase C beta (PLC-beta). PLC-beta catalyzes hydrolysis of Phosphoinositide 4,5-bisphosphate (PI(4,5)P2) into Inositol 1,4,5-triphosphate (IP3) and Diacylglycerol (DAG). IP3 released into the cytoplasm mobilizes Ca(II) from internal stores, whereas DAG activates Protein kinase C epsilon (PKC-epsilon). PKC-epsilon induces PTK2B protein tyrosine kinase 2 beta (PYK2) activation and stimulation of PKC-epsilon/PYK2/Vav 1 guanine nucleotide exchange factor (VAV-1)/ Cell division cycle 42 (Cdc42)/Mitogen-activated protein kinase kinase kinase 4 (MEKK4)/Mitogen-activated protein kinase kinase 3 (MEK3) pathway [4]. Stimulation of Adenosine A2B receptor can activate p38MAPK via cAMP/PKA/ Rho guanine nucleotide exchange factor 7 (BETA-PIX) pathway [5]. p38MAPK, possibly Nuclear factor kappa B (NF-kB), and CCAAT/enhancer binding protein beta (C/EBPbeta) activate transcription of IL-6 [6].

Human Adenosine A2B receptors mediate phosphorylation and activation of the Extracellular signal-regulated kinase (ERK) via cAMP/Rap guanine nucleotide exchange factor 3 (AMP-GEF1)/RAP1A member of RAS oncogene family (RAP-1A)/Small nuclear ribonucleoprotein polypeptide E (B-Raf) pathway [5].

Adenosine induces NO production by Nitric oxide synthase 3 (eNOS), whose activation is initiated by Phosphoinositide-3-kinase (PI3K)/V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) pathway and ERK/ ELK1 member of ETS oncogene family (Elk-1)-dependent transcription. Upon activation by cAMP, guanine nucleotide exchange factor Rap guanine nucleotide exchange factor 2 (PDZ-GEF) stimulates PI3K activation via v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras). PI3K converts Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) [7]. PtdIns(3,4,5)P3 is a second messenger that directly binds to and AKT. AKT phosphorylates and activates eNOS [8].

References:

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. 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
3. Lynge J, Schulte G, Nordsborg N, Fredholm BB, Hellsten Y
   Adenosine A 2B receptors modulate cAMP levels and induce CREB but not ERK1/2 and p38 phosphorylation in rat skeletal muscle cells. Biochemical and biophysical research communications 2003 Jul 18;307(1):180-7
4. Fiebich BL, Akundi RS, Biber K, Hamke M, Schmidt C, Butcher RD, van Calker D, Willmroth F
   IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C. Neurochemistry international 2005 May;46(6):501-12
5. Schulte G, Fredholm BB
   The G(s)-coupled adenosine A(2B) receptor recruits divergent pathways to regulate ERK1/2 and p38. Experimental cell research 2003 Oct 15;290(1):168-76
6. Schwaninger M, Neher M, Viegas E, Schneider A, Spranger M
   Stimulation of interleukin-6 secretion and gene transcription in primary astrocytes by adenosine. Journal of neurochemistry 1997 Sep;69(3):1145-50
7. 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
8. Xu Z, Park SS, Mueller RA, Bagnell RC, Patterson C, Boysen PG
   Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes. Cardiovascular research 2005 Mar 1;65(4):803-12