Phosphatidylinositol 3-kinase offsets cAMP-mediated positive inotropic effect via inhibiting Ca2+ influx in cardiomyocytes

Veronique Leblais, Su Hyun Jo, Khalid Chakir, Victor Maltsev, Ming Zheng, Michael T. Crow, Wang Wang, Edward G. Lakatta, Rui Ping Xiao

Research output: Contribution to journalArticle

Abstract

Phosphoinositide 3-kinase (PI3K) has been implicated in β2-adrenergic receptor (β2-AR)/G i-mediated compartmentation of the concurrent Gs-cAMP signaling, negating β2-AR-induced phospholamban phosphorylation and the positive inotropic and lusitropic responses in cardiomyocytes. However, it is unclear whether PI3K crosstalks with the β1-AR signal transduction, and even more generally, with the cAMP/PKA pathway. In this study, we show that selective β1-AR stimulation markedly increases PI3K activity in adult rat cardiomyocytes. Inhibition of PI3K by LY294002 significantly enhances β1-AR-induced increases in L-type Ca 2+ currents, intracellular Ca2+ transients, and myocyte contractility, without altering the receptor-mediated phosphorylation of phospholamban. The LY294002 potentiating effects are completely prevented by βARK-ct, a peptide inhibitor of β-adrenergic receptor kinase-1 (βARK1) as well as Gβγ signaling, but not by disrupting Gi function with pertussis toxin. Moreover, forskolin, an adenylyl cyclase activator, also elevates PI3K activity and inhibition of PI3K enhances forskolin-induced contractile response in a βARK-ct sensitive manner. In contrast, PI3K inhibition affects neither the basal contractility nor high extracellular Ca2+-induced increase in myocyte contraction. These results suggest that β1-AR stimulation activates PI3K via a PKA-dependent mechanism, and that Gβγ and the subsequent activation of βARK1 are critically involved in the PKA-induced PI3K signaling which, in turn, negates cAMP-induced positive inotropic effect via inhibiting sarcolemmal Ca2+ influx and the subsequent increase in intracellular Ca2+ transients, without altering the receptor-mediated phospholamban phosphorylation, in intact cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)1183-1190
Number of pages8
JournalCirculation research
Volume95
Issue number12
DOIs
StatePublished - Dec 10 2004

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Keywords

  • Cardiac contractility
  • L-type calcium current
  • PI3K
  • PKA
  • β- adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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