Phosphatidylinositol 3-Kinase Functionally Compartmentalizes the Concurrent G s Signaling During β 2 -Adrenergic Stimulation
| Autor: | Rui-Ping Xiao, Su Hyun Jo, Veronique Leblais, Michael T. Crow, Ping H. Wang |
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| Rok vydání: | 2002 |
| Předmět: |
Physiology
G protein Heart Ventricles Morpholines Adrenergic beta-Antagonists Biology Pertussis toxin Wortmannin Phosphatidylinositol 3-Kinases chemistry.chemical_compound Cyclic AMP GTP-Binding Protein alpha Subunits Gs Serine Animals Phosphatidylinositol Enzyme Inhibitors Insulin-Like Growth Factor I Phosphorylation Protein kinase A Cells Cultured Cell Size Phosphoinositide-3 Kinase Inhibitors G protein-coupled receptor Calcium-Binding Proteins Imidazoles Adrenergic beta-Agonists Cyclic AMP-Dependent Protein Kinases Heterotrimeric GTP-Binding Proteins Rats Cell biology Androstadienes chemistry Biochemistry Chromones Ethanolamines Calcium Receptors Adrenergic beta-2 Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Circulation Research. 91:46-53 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | 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 β 2 -adrenoceptor (β 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 β 2 -AR-coupled G i proteins has been implicated in the functional compartmentation of PKA signaling, the exact mechanism underlying the restriction of the β 2 -AR-PKA pathway remains unclear. In the present study, we demonstrate that phosphatidylinositol 3-kinase (PI3K) plays an essential role in confining the β 2 -AR-PKA signaling. Inhibition of PI3K with LY294002 or wortmannin enables β 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 β 2 -AR-induced cAMP formation. Blocking G i or Gβγ signaling with pertussis toxin or βARK-ct, a peptide inhibitor of Gβγ, completely prevents the potentiating effects induced by PI3K inhibition, indicating that the pathway responsible for the functional compartmentation of β 2 -AR-PKA signaling sequentially involves G i , Gβγ, and PI3K. Thus, PI3K constitutes a key downstream event of β 2 -AR-G i signaling, which confines and negates the concurrent β 2 -AR/G s -mediated PKA signaling. |
| Databáze: | OpenAIRE |
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