Development - A3 receptor signaling

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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:

  1. Headrick JP, Peart J
    A3 adenosine receptor-mediated protection of the ischemic heart. Vascular pharmacology 2005 Apr-May;42(5-6):271-9
  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. 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
  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
  5. 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
  6. 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
  7. 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

  1. Headrick JP, Peart J
    A3 adenosine receptor-mediated protection of the ischemic heart. Vascular pharmacology 2005 Apr-May;42(5-6):271-9
  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. 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
  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
  5. 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
  6. 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
  7. 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

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