Published online before print May 30, 2002, doi: 10.1161/01.RES.0000024115.67561.54
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© 2002 American Heart Association, Inc.
Cellular Biology |
Phosphatidylinositol 3-Kinase Functionally Compartmentalizes the Concurrent Gs Signaling During ß2-Adrenergic Stimulation
From the Laboratory of Cardiovascular Science (S.-H.J., V.L., M.T.C., R.-P.X.), Gerontology Research Center, National Institute on Aging, National Institute of Health, Baltimore, Md; and the Department of Medicine and Biological Chemistry (P.H.W), Division of Endocrinology, Diabetes, and Metabolism, University of California, Irvine, Calif.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail XiaoR{at}grc.nia.nih.gov
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 ß2-adrenoceptor (ß2-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 ß2-AR-coupled Gi proteins has been implicated in the functional compartmentation of PKA signaling, the exact mechanism underlying the restriction of the ß2-AR-PKA pathway remains unclear. In the present study, we demonstrate that phosphatidylinositol 3-kinase (PI3K) plays an essential role in confining the ß2-AR-PKA signaling. Inhibition of PI3K with LY294002 or wortmannin enables ß2-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 ß2-AR-induced cAMP formation. Blocking Gi or Gß
signaling with pertussis toxin or ßARK-ct, a peptide inhibitor of Gß, completely prevents the potentiating effects induced by PI3K inhibition, indicating that the pathway responsible for the functional compartmentation of ß2-AR-PKA signaling sequentially involves Gi, Gß, and PI3K. Thus, PI3K constitutes a key downstream event of ß2-AR-Gi signaling, which confines and negates the concurrent ß2-AR/Gs-mediated PKA signaling.
Key Words: ß2-adrenoceptor • cAMP signal compartmentation • phosphatidylinositol 3-kinase • phospholamban • cardiac contractility
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