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  • Title: The G(s)-coupled adenosine A(2B) receptor recruits divergent pathways to regulate ERK1/2 and p38.
    Author: Schulte G, Fredholm BB.
    Journal: Exp Cell Res; 2003 Oct 15; 290(1):168-76. PubMed ID: 14516797.
    Abstract:
    Adenosine A(2B) receptors have been suggested to influence cell differentiation and proliferation. Human adenosine A(2B) receptors expressed in Chinese hamster ovary cells mediate phosphorylation and activation of the extracellular signal-regulated kinase (ERK1/2). Already low concentrations of agonists such as 5'-N-ethylcarboxamidoadenosine (NECA) are effective. Phosphorylation of the stress-activated protein kinase p38 was also potently induced by NECA (EC(50) 18.5 nM). These NECA-induced effects were mimicked by forskolin and 8-Br-cAMP. Inhibition of cAMP-dependent protein kinase (PKA) using H89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide)) blocked phosphorylation of the cAMP response element-binding protein (CREB) and p38, but did not decrease NECA-induced ERK1/2 phosphorylation. NECA activated the small GTPase Rap1, and this was also not blocked by H89. Inhibition of phosphatidylinositol-3'-kinase (PI3K) by wortmannin inhibited adenosine A(2B) receptor-mediated ERK1/2 phosphorylation and activation of Rap1, without affecting CREB and p38 phosphorylation. A(2B) receptor-stimulated protein kinase B phosphorylation was sensitive to wortmannin, but not to H89. Thus, stimulation of adenosine A(2B) receptors activates both ERK1/2 and p38 via cAMP, but the downstream pathways are markedly different. ERK1/2 activation was dependent on PI3K but not on PKA. p38 activation by NECA was instead independent of PI3K but required cAMP and PKA. The potent activation of both MAPKs suggests a physiological role.
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