Development - A1 receptor signaling

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Adenosine A1 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 A1 receptor is a G-protein alpha-i and G-protein alpha-15 coupled receptor [1].

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

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

Phospholipase C, beta 3 (PLC-beta3) activation is coupled with Adenosine A1 receptor signaling via both G-protein alpha-15 and G-proteins beta/gamma subunits. PLC-beta3 catalyzes hydrolysis of phosphoinositide 4,5-bisphosphate (PtdIns(4,5)P2) to form inositol 1,4,5-triphosphate (IP3) and 1,2-diacyl-glycerol (DAG). The IP3 is 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 in the Adenosine A1 receptor signaling via activation of Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKK-beta)/ 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) 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 messenger phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) stimulate Phosphatidylinositol-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 (P38 MAPK) is activated by Rac1 via Mitogen-activated protein kinase kinase kinase 4 (MEKK4(MAP3K4))/ Mitogen-activated protein kinase kinase 3 (MEK3(MAP2K3)) pathway.

The G-protein beta/gamma heterodimers activate PI3K cat class IB, recruiting Phosphoinositide-3-kinase, regulatory subunit 5 (PI3K reg class IB (p101)) that activates Phosphoinositide-3-kinase, catalytic, gamma polypeptide (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)), that activates Conserved helix-loop-helix ubiquitous kinase (IKK-alpha)/I-kB/NF-kB signaling [6].

The Adenosine A1 receptor activates Mitogen-activated protein kinase 1-3 (ERK1/2) pathway via the activation of G-protein beta/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 oncogene homolog 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 domain containing) transforming protein 1 (Shc), and recruitment of adaptor protein Growth factor receptor-bound protein 2 (GRB2) and Son of sevenless homolog (SOS) [7].

References:

  1. Liu AM, Wong YH
    G16-mediated activation of nuclear factor kappaB by the adenosine A1 receptor involves c-Src, protein kinase C, and ERK signaling. The Journal of biological chemistry 2004 Dec 17;279(51):53196-204
  2. 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
  3. Dickenson JM, Hill SJ
    Transfected adenosine A1 receptor-mediated modulation of thrombin-stimulated phospholipase C and phospholipase A2 activity in CHO cells. European journal of pharmacology 1997 Feb 19;321(1):77-86
  4. Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC, Hawkins PT, Stephens LR
    Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. The Journal of biological chemistry 2005 Feb 11;280(6):4166-73
  5. 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
  6. Igarashi J, Michel T
    Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways. The Journal of biological chemistry 2001 Sep 28;276(39):36281-8
  7. Schulte G, Fredholm BB
    Signalling from adenosine receptors to mitogen-activated protein kinases. Cellular signalling 2003 Sep;15(9):813-27

  1. Liu AM, Wong YH
    G16-mediated activation of nuclear factor kappaB by the adenosine A1 receptor involves c-Src, protein kinase C, and ERK signaling. The Journal of biological chemistry 2004 Dec 17;279(51):53196-204
  2. 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
  3. Dickenson JM, Hill SJ
    Transfected adenosine A1 receptor-mediated modulation of thrombin-stimulated phospholipase C and phospholipase A2 activity in CHO cells. European journal of pharmacology 1997 Feb 19;321(1):77-86
  4. Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC, Hawkins PT, Stephens LR
    Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. The Journal of biological chemistry 2005 Feb 11;280(6):4166-73
  5. 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
  6. Igarashi J, Michel T
    Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways. The Journal of biological chemistry 2001 Sep 28;276(39):36281-8
  7. Schulte G, Fredholm BB
    Signalling from adenosine receptors to mitogen-activated protein kinases. Cellular signalling 2003 Sep;15(9):813-27

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