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The G(s)-coupled adenosine A(2B) receptor recruits divergent pathways to regulate ERK1/2 and p38

Gunnar Schulte1, Bertil B Fredholm

  • 1Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden. gunnar.schulte@fyfa.ki.se

Experimental Cell Research
|October 1, 2003
PubMed

Insights

Adenosine A(2B) receptors activate key signaling pathways like ERK1/2 and p38. These pathways have distinct downstream mechanisms involving PI3K and PKA, suggesting a significant physiological role.

Area of Science:

  • Cellular signaling
  • Molecular pharmacology
  • Receptor biology

Background:

  • Adenosine A(2B) receptors are implicated in cell differentiation and proliferation.
  • Understanding their signaling pathways is crucial for elucidating their physiological roles.

Purpose of the Study:

  • To investigate the downstream signaling pathways activated by human adenosine A(2B) receptors.
  • To differentiate the roles of cAMP-dependent protein kinase (PKA) and phosphatidylinositol-3'-kinase (PI3K) in mediating these effects.

Main Methods:

  • Expression of human adenosine A(2B) receptors in Chinese hamster ovary cells.
  • Stimulation with agonists like 5'-N-ethylcarboxamidoadenosine (NECA) and modulators like forskolin and 8-Br-cAMP.
  • Inhibition studies using H89 (PKA inhibitor) and wortmannin (PI3K inhibitor).
  • Analysis of extracellular signal-regulated kinase (ERK1/2), stress-activated protein kinase p38, cAMP response element-binding protein (CREB), Rap1, and protein kinase B (Akt) phosphorylation.

Main Results:

  • NECA potently activated ERK1/2 and p38 phosphorylation.
  • ERK1/2 activation was dependent on PI3K but not PKA.
  • p38 activation required cAMP and PKA, but not PI3K.
  • NECA also activated Rap1 and protein kinase B, with distinct dependencies on PI3K and PKA.

Conclusions:

  • Adenosine A(2B) receptor stimulation activates both ERK1/2 and p38 via cAMP, but through markedly different downstream pathways.
  • ERK1/2 signaling involves PI3K, while p38 signaling involves PKA.
  • The potent activation of these mitogen-activated protein kinases (MAPKs) suggests a significant physiological function for adenosine A(2B) receptors.

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