Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
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Lipid phosphatase
Generic phospholipase
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RAS - superfamily
G beta/gamma
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Ligand-gated channel
Voltage-gated channel
Normal process
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Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
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MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
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Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

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].