Phosphatidylinositol 3-Kinase Offsets Camp-Mediated Positive Inotropic Effect Via Inhibiting Ca2+ Influx In Cardiomyocytes
CIRCULATION RESEARCH(2004)
摘要
Phosphoinositide 3-kinase (PI3K) has been implicated in beta(2)-adrenergic receptor (beta(2)-AR)/G(i)-mediated compartmentation of the concurrent G(s)-cAMP signaling, negating beta(2)-AR-induced phospholamban phosphorylation and the positive inotropic and lusitropic responses in cardiomyocytes. However, it is unclear whether PI3K crosstalks with the beta(1)-AR signal transduction, and even more generally, with the cAMP/PKA pathway. In this study, we show that selective beta(1)-AR stimulation markedly increases PI3K activity in adult rat cardiomyocytes. Inhibition of PI3K by LY294002 significantly enhances beta(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 betaARK-ct, a peptide inhibitor of beta-adrenergic receptor kinase-1 (betaARK1) as well as G(betagamma) 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 betaARK-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 beta(1)-AR stimulation activates PI3K via a PKA-dependent mechanism, and that G(betagamma) and the subsequent activation of betaARK1 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.
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关键词
PI3K, PKA, cardiac contractility, L-type calcium current, beta(1)-adrenergic receptor
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