Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent Gs signaling during β2-adrenergic stimulation

Su Hyun Jo, Veronique Leblais, Ping H. Wang, Michael T. Crow, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

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 β2-adrenoceptor (β2-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 β2-AR-coupled Gi proteins has been implicated in the functional compartmentation of PKA signaling, the exact mechanism underlying the restriction of the β2-AR-PKA pathway remains unclear. In the present study, we demonstrate that phosphatidylinositol 3-kinase (PI3K) plays an essential role in confining the β2-AR-PKA signaling. Inhibition of PI3K with LY294002 or wortmannin enables β2-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 β2-AR-induced CAMP formation. Blocking Gi 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 β2-AR-PKA signaling sequentially involves Gi, Gβγ, and PI3K. Thus, PI3K constitutes a key downstream event of β2-AR-Gi signaling, which confines and negates the concurrent β2-AR/Gs-mediated PKA signaling.

Original languageEnglish (US)
Pages (from-to)46-53
Number of pages8
JournalCirculation research
Volume91
Issue number1
DOIs
StatePublished - Jul 12 2002

Keywords

  • Cardiac contractility
  • Phosphatidylinositol 3-kinase
  • Phospholamban
  • cAMP signal compartmentation
  • β-adrenoceptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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