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(Circulation Research. 2004;95:1183.)
© 2004 American Heart Association, Inc.

Cellular Biology

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

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.

Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail XiaoR{at}grc.nia.nih.gov

Phosphoinositide 3-kinase (PI3K) has been implicated in ß₂-adrenergic receptor (ß₂-AR)/G_i-mediated compartmentation of the concurrent G_s-cAMP signaling, negating ß₂-AR–induced phospholamban phosphorylation and the positive inotropic and lusitropic responses in cardiomyocytes. However, it is unclear whether PI3K crosstalks with the ß₁-AR signal transduction, and even more generally, with the cAMP/PKA pathway. In this study, we show that selective ß₁-AR stimulation markedly increases PI3K activity in adult rat cardiomyocytes. Inhibition of PI3K by LY294002 significantly enhances ß₁-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 ßARK-ct, a peptide inhibitor of ß-adrenergic receptor kinase-1 (ßARK1) as well as G_ß signaling, but not by disrupting G_i 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 ßARK-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 ß₁-AR stimulation activates PI3K via a PKA-dependent mechanism, and that G_ß and the subsequent activation of ßARK1 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 • ß₁-adrenergic receptor

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