期刊
CIRCULATION RESEARCH
卷 91, 期 1, 页码 46-53出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000024115.67561.54
关键词
beta(2)-adrenoceptor; cAMP signal compartmentation; phosphatidylinositol 3-kinase; phospholamban; cardiac contractility
Compartmentation of intracellular signaling pathways serves as an important mechanism conferring the specificity of G protein-coupled receptor (GPCR) signaling. In the heart, stimulation Of beta(2)-adrenoceptor (beta(2)-AR), a prototypical GPCR, activates a tightly localized protein kinase A (PKA) signaling, which regulates substrates at cell surface membranes, bypassing cytosolic target proteins (ca, phospholamban). Although a concurrent activation of beta(2)-AR-coupled G, proteins has been implicated in the functional compartmentation of PKA signaling, the exact mechanism underlying the restriction of the beta(2)-AR-PKA pathway remains unclear. In the present study, we demonstrate that phosphatidylinositol 3-kinase (PI3K) plays an essential role in confining the beta(2)-AR-PKA signaling. Inhibition of PI3K with LY294002 or wortmannin enables beta(2)-AR-PKA signaling to reach intracellular substrates, as manifested by a robust increase in phosphorylation of phospholamban, and markedly enhances the receptor-mediated positive contractile and relaxant responses in cardiac myocytes. These potentiating effects of PI3K inhibitors are not accompanied by an increase in beta(2)-AR-induced cAMP formation. Blocking G, or GOT signaling with pertussis toxin or betaARK-ct, a peptide inhibitor of GOT, completely prevents the potentiating effects induced by PI3K inhibition, indicating that the pathway responsible for the functional compartmentation Of beta(2)-AR-PKA signaling sequentially involves G(i), Gbetagamma, and PI3K. Thus, PI3K constitutes a key downstream event of beta(2)-AR-G, signaling, which confines and negates the concurrent beta(2)-AR/G(s)-mediated PKA signaling.
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