Published online before print November 11, 2004, doi: 10.1161/01.RES.0000150049.74539.8a
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Submitted on June 3, 2004
Revised on October 18, 2004
Accepted on October 28, 2004
Phosphatidylinositol 3-Kinase Offsets cAMP-Mediated Positive Inotropic Effect via Inhibiting Ca2+ Influx in Cardiomyocytes
Veronique Leblais ;
From the Laboratory of Cardiovascular Science (V.L., S.-H.J., K.C., V.M., M.Z., M.T.C., W.W., E.G.L., R.-P.X.), Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Md; The Institute of Molecular Medicine and The Institute of Cardiovascular Sciences (M.Z., R.-P.X.), Peking University, Beijing, China. Present address for V.L. is Laboratoire de Pharmacologie de l’UFR de Pharmacie & INSERM EMI0356, Université Victor Segalen Bordeaux 2, Bordeaux, France; and for S.-H.J., Department of Physiology, Cheju National University College of Medicine, Ara 1-Dong, Jeju, Korea.
* To whom correspondence should be addressed. E-mail: XiaoR{at}grc.nia.nih.gov.
Phosphoinositide 3-kinase (PI3K) has been implicated in 
2-adrenergic receptor (2-AR)/Gi-mediated compartmentation of the concurrent Gs-cAMP signaling, negating 2-AR-induced phospholamban phosphorylation and the positive inotropic and lusitropic responses in cardiomyocytes. However, it is unclear whether PI3K crosstalks with the 1-AR signal transduction, and even more generally, with the cAMP/PKA pathway. In this study, we show that selective 1-AR stimulation markedly increases PI3K activity in adult rat cardiomyocytes. Inhibition of PI3K by LY294002 significantly enhances 1-AR-induced increases in L-type Ca2+ currents, intracellular Ca2+ transients, and myocyte contractility, without altering the receptor-mediated phosphorylation of phospholamban. The LY294002 potentiating effects are completely prevented by ARK-ct, a peptide inhibitor of -adrenergic receptor kinase-1 (ARK1) as well as G
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 ARK-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 1-AR stimulation activates PI3K via a PKA-dependent mechanism, and that G and the subsequent activation of ARK1 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.
Key words: PI3K • PKA • cardiac contractility • L-type calcium current •
1-adrenergic receptor
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