Adenosine A1 and A2A receptor regulation of protein phosphatase 2A in the murine heart

Abstract

Adenosine plays a role in regulating the contractile function of the heart. This includes a positive ionotropic action via the adenosine A(2A) receptor (A(2A)R) and an inhibition of beta(1)-adrenergic receptor-induced ionotropy (antiadrenergic action) via the adenosine A(1) receptor (A(1)R). Phosphatase activity has also been shown to influence contractile function by affecting the level of protein phosphorylation. Protein phosphatase 2A (PP2A) plays a significant role in mediating the A(1)R antiadrenergic effect. The purpose of this study was to investigate the effects of A(2A)R and A(1)R on the activities of PP2A in hearts obtained from wild-type (WT) and A(2A)R knockout (A(2A)R-KO) mice. PP2A activities were examined in myocardial particulate and cytoplasmic extract fractions. Treatment of wild-type hearts with the A(1)R agonist CCPA increased the total PP2A activity and increased the particulate:cytoplasmic PP2A activity ratio. Treatment with the A(2A)R agonist CGS-21680 (CGS) decreased the total PP2A activity and decreased the particulate:cytoplasmic PP2A activity ratio. This indicated a movement of PP2A activity between cell fractions. The effect of CCPA was inhibited by CGS. In A(2A)R-KO hearts the response to A(1)R activation was markedly enhanced whereas the response to A(2A)R activation was absent. These data show that A(2A)R and A(1)R regulate PP2A activity, thus suggesting an important mechanism for modulating myocardial contractility.