Phosphatidylinositol 3-Kinase Functionally Compartmentalizes the Concurrent GsSignaling During &bgr;2-Adrenergic Stimulation
作者:
Su-Hyun Jo,
Veronique Leblais,
Ping Wang,
Michael Crow,
Rui-Ping Xiao,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2002)
卷期:
Volume 91,
issue 1
页码: 46-53
ISSN:0009-7330
年代: 2002
出版商: OVID
关键词: &bgr;2-adrenoceptor;cAMP signal compartmentation;phosphatidylinositol 3-kinase;phospholamban;cardiac contractility
数据来源: OVID
摘要:
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 &bgr;2-adrenoceptor (&bgr;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 (eg, phospholamban). Although a concurrent activation of &bgr;2-AR-coupled Giproteins has been implicated in the functional compartmentation of PKA signaling, the exact mechanism underlying the restriction of the &bgr;2-AR-PKA pathway remains unclear. In the present study, we demonstrate that phosphatidylinositol 3-kinase (PI3K) plays an essential role in confining the &bgr;2-AR-PKA signaling. Inhibition of PI3K with LY294002 or wortmannin enables &bgr;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 &bgr;2-AR-induced cAMP formation. Blocking Gior G&bgr;&ggr; signaling with pertussis toxin or &bgr;ARK-ct, a peptide inhibitor of G&bgr;&ggr;, completely prevents the potentiating effects induced by PI3K inhibition, indicating that the pathway responsible for the functional compartmentation of &bgr;2-AR-PKA signaling sequentially involves Gi, G&bgr;&ggr;, and PI3K. Thus, PI3K constitutes a key downstream event of &bgr;2-AR-Gisignaling, which confines and negates the concurrent &bgr;2-AR/Gs-mediated PKA signaling.
点击下载:
PDF
(217KB)
返 回