Gi Protein-mediated Functional Compartmentalization of Cardiac β2-Adrenergic Signaling

• Published in: The Journal of biological chemistry 1999-07, Vol.274 (31), p.22048-22052
• Main Authors: Kuschel, Meike, Zhou, Ying-Ying, Cheng, Heping, Zhang, Sheng-Jun, Chen, Ye, Lakatta, Edward G., Xiao, Rui-Ping
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.31.22048

In contrast to β1-adrenoreceptor (β1-AR) signaling, β2-AR stimulation in cardiomyocytes augmentsl-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 Gi 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 β1-AR. Thus, β2-AR-mediated Gi activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not significantly affect the β2-AR-stimulated PKA activation. Similar to Gi inhibition, a protein phosphatase inhibitor, calyculin A (3 × 10−8m), 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 Gi and Gs signaling affects the local balance of protein kinase and phosphatase activities. Thus, the additional coupling of β2-AR to Giproteins is a key factor causing the compartmentalization of β2-AR-induced cAMP signaling.