Adenosine A3 receptor-mediated regulation of p38 and extracellular-regulated kinase ERK1/2 via phosphatidylinositol-3'-kinase

Biochem Pharmacol. 2004 Jan 1;67(1):129-34. doi: 10.1016/j.bcp.2003.08.031.

Abstract

The adenosine A(3) receptor generally couples to the G(i) class of heterotrimeric G proteins, thereby decreasing cAMP levels and also mediating signaling via release of betagamma subunits. Here we describe the central role of phosphatidylinositol-3'-kinase (PI3K) for adenosine A(3) receptor-induced intracellular signaling to the stress-activated protein kinase p38 and the extracellular signal-regulated protein kinases ERK1/2. We used Chinese hamster ovary cells expressing the human adenosine A(3) receptor, phospho-specific antibodies and different pharmacological tools to dissect the signaling pathways involving PI3K. The adenosine receptor agonist 5'N-ethylcarboxamidoadenosine induced a time- and dose-dependent increase in p38 and ERK1/2 phosphorylation, two signaling pathways that appeared also to be activated in the immortalized microglia cell line N13, which expressed endogenous adenosine A(3) receptors. The 5'N-ethylcarboxamidoadenosine-induced effects on p38 and ERK1/2 in CHO cells were blocked by pertussis toxin pretreatment and were sensitive to pharmacological inhibition of PI3K. In addition, inhibition of Rac/Cdc42, small GTPases of the Rho family, by clostridium toxin B, diminished p38 phosphorylation but did not affect ERK1/2. Furthermore, we identified the serine 727 site of signal transducer and activator of transcription STAT3 as a probable downstream target of ERK1/2, and thereby provide evidence that adenosine A(3) receptor mediated ERK1/2 activation has functional consequences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • GTP-Binding Protein alpha Subunits, Gi-Go / physiology
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Receptor, Adenosine A3 / metabolism*
  • STAT3 Transcription Factor
  • Serine / metabolism
  • Time Factors
  • Trans-Activators / metabolism
  • cdc42 GTP-Binding Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • DNA-Binding Proteins
  • Receptor, Adenosine A3
  • STAT3 Transcription Factor
  • Trans-Activators
  • Serine
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • cdc42 GTP-Binding Protein