A_2B adenosine receptor activation and modulation by protein kinase C

Protein kinase C (PKC) isoforms regulate many important signaling pathways. Here, we report that PKC activation by phorbol 12-myristate 13-acetate (PMA) enhanced A_2B adenosine receptor (AR)-mediated, but not β₂-adrenergic receptor-mediated, cAMP accumulation, in H9C2 cardiomyocyte-like and HEK293 cells. In addition to enhancement, PKC (PMA-treatment) also activated A_2BAR with low E_max (H9C2 and NIH3T3 cells endogenously expressing A_2BAR), or with high E_max (A_2BAR-overexpressing HEK293 cells) to induce cAMP accumulation. A_2BAR activation induced by PKC was inhibited by A_2BAR and PKC inhibitors but enhanced by A_2BAR overexpression. Gαi isoforms and PKCγ isoform were found to be involved in both enhancement of A_2BAR function and A_2BAR activation. Thus, we establish PKC as an endogenous modulator and activator of A_2BAR, involving G_iα and PKCγ. Depending on signaling pathway, PKC could activate and enhance, or alternatively inhibit A_2BAR activity. These findings are relevant to common functions of A_2BAR and PKC, e.g. cardioprotection and cancer progression/treatment.