In contrast to β1-adrenoreceptor (β1-AR) signaling, β2-AR stimulation in cardiomyocytes augments L-type Ca2+ current in a cAMP- dependent protein kinase (PKA)dependent manner but fails to phosphorylate phospholamban, indicating that the β2-AR-induced cAMP/PKA signaling is highly localized. Here we show that inhibition of G(i) proteins with pertussis toxin (PTX) permits a full phospholamban phosphorylation and a de novo relaxant effect following β2-AR stimulation, converting the localized β2-AR signaling to a global signaling mode similar to that of 131-AR. Thus, β2-AR-mediated G(i) activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not significantly affect the β2-AR-stimulated PKA activation. Similar to G(i) inhibition, a protein phosphatase inhibitor, calyculin A (3 x 10-8 M), selectively enhanced the β2-AR but not β1-AR- mediated contractile response. Furthermore, PTX and calyculin A treatment had a non-additive potentiating effect on the β2-AR-mediated positive inotropic response. These results suggest that the interaction of the β2-AR-coupled G(i) and G(s) signaling affects the local balance of protein kinase and phosphatase activities. Thus, the additional coupling of β2-AR to G(i) proteins is a key factor causing the compartmentalization of β2-AR-induced cAMP signaling.
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