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Development A1 receptor signaling


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Development A1 receptor signaling

Adenosine A1 receptor signaling

Adenosine is a potent biological mediator that affects numerouscell 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 surfacereceptors. Adenosine A1 receptor is a G-protein alpha-i andG-protein alpha-15 coupled receptor [1].

Adenosine A1 receptor interaction with the trimeric G-proteinalpha/beta/gamma causes the exchange of GDP to GTP bound to G-protein alphasubunits and the dissociation of the beta/gamma heterodimers.

G-protein alpha-i inhibits activity of several Adenylatecyclase isoforms that leads to the decrease of cAMP level and attenuation ofcAMP responsive element binding protein 1 ( CREB1 ) phosphorylation by Proteinkinase, cAMP-dependent, catalytic ( PKA-cat (cAMP-dependent) ) [2].

Phospholipase C, beta 3 ( PLC-beta3 ) activation is coupled withAdenosine A1 receptor signaling via both G-protein alpha-15 andG-proteins beta/gamma subunits. PLC-beta3 catalyzes hydrolysis ofphosphoinositide 4,5-bisphosphate ( PtdIns(4,5)P2 ) to form inositol1,4,5-triphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG ). The IP3is then released into the cytoplasm and mobilizes Ca('2+) from internal stores,whereas DAG activates Protein kinase C delta ( PKC-delta ), which,stimulates Protein kinase D1 ( PKC-mu ) . PKC-mu plays an important role inthe Adenosine A1 receptor signaling via activation of Inhibitor of kappalight polypeptide gene enhancer in B-cells, kinase beta ( IKK-beta)/ Nuclearfactor 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 )pathway [1].

DAG and Ca(II) can also activate Protein kinase C, alpha( PKC-alpha ). PKC-alpha regulates Phospholipase A2, group IVA (PA24A )-mediated Arachidonic acid release independently of MAP kinase[3].

G-proteins beta/gamma subunits and the lipid second messengerphosphatidylinositol (3,4,5)-trisphosphate ( PtdIns(3,4,5)P3 ) stimulatePhosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 ( PREX1 )Rac-GEF activity. PREX1 is a Ras-related C3 botulinum toxin substrate 1 (Rac1 ) activator [4]. Mitogen-activated protein kinase 14 ( P38MAPK ) is activated by Rac1 via Mitogen-activated protein kinase kinase kinase4 ( MEKK4(MAP3K4) )/ Mitogen-activated protein kinase kinase 3 (MEK3(MAP2K3) ) pathway.

The G-protein beta/gamma heterodimers activate PI3Kcat class IB, recruiting Phosphoinositide-3-kinase, regulatory subunit 5 ( PI3Kreg class IB (p101) ) that activates Phosphoinositide-3-kinase, catalytic, gammapolypeptide ( PI3K cat class IB (p110-gamma) ). PI3K cat class IB(p110-gamma) converts phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 )to phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) [5].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) ), thatactivates Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha )/ I-kB/ NF-kB signaling [6].

The Adenosine A1 receptor activates Mitogen-activatedprotein kinase 1-3 ( ERK1/2 ) pathway via the activation of G-proteinbeta/gamma and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-Src ). In turn, c-Src activates v-raf-1 murine leukemia viral oncogenehomolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2) )/ ERK1/2/ ELK1, member of ETS oncogene family( ELK1 ) pathway via phosphorylation of adaptor protein SHC (Src homology 2 domaincontaining) transforming protein 1 ( Shc ), and recruitment of adaptor proteinGrowth factor receptor-bound protein 2 ( GRB2 ) and Son of sevenless homolog (SOS ) [7].