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学科主题基础医学
Phosphatidylinositol 3-kinase offsets cAMP-mediated positive inotropic effect via inhibiting Ca2+ influx in cardiomyocytes
Leblais, V; Jo, SH; Chakir, K; Maltsev, V; Zheng, M; Crow, MT; Wang, W; Lakatta, EG; Xiao, RP
关键词PI3K PKA cardiac contractility L-type calcium current beta(1)-adrenergic receptor
刊名CIRCULATION RESEARCH
2004-12-10
DOI10.1161/01.RES.0000150049.74539.8a
95期:12页:1183-1190
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cardiac & Cardiovascular Systems ; Hematology ; Peripheral Vascular Disease
研究领域[WOS]Cardiovascular System & Cardiology ; Hematology
关键词[WOS]COUPLED RECEPTOR KINASES ; CARDIAC MYOCYTES ; PHOSPHOINOSITIDE 3-KINASE ; G-PROTEIN ; PERTUSSIS-TOXIN ; MYOCARDIAL-CONTRACTILITY ; ADENYLYL-CYCLASE ; UP-REGULATION ; CELL-DEATH ; RAT-HEART
英文摘要

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.

语种英语
WOS记录号WOS:000225641000007
Citation statistics
Cited Times:43[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/62309
Collection北京大学基础医学院_心血管所
作者单位1.NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA
2.Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China
3.Peking Univ, Inst Cardiovasc Sci, Beijing 100871, Peoples R China
Recommended Citation
GB/T 7714
Leblais, V,Jo, SH,Chakir, K,et al. Phosphatidylinositol 3-kinase offsets cAMP-mediated positive inotropic effect via inhibiting Ca2+ influx in cardiomyocytes[J]. CIRCULATION RESEARCH,2004,95(12):1183-1190.
APA Leblais, V.,Jo, SH.,Chakir, K.,Maltsev, V.,Zheng, M.,...&Xiao, RP.(2004).Phosphatidylinositol 3-kinase offsets cAMP-mediated positive inotropic effect via inhibiting Ca2+ influx in cardiomyocytes.CIRCULATION RESEARCH,95(12),1183-1190.
MLA Leblais, V,et al."Phosphatidylinositol 3-kinase offsets cAMP-mediated positive inotropic effect via inhibiting Ca2+ influx in cardiomyocytes".CIRCULATION RESEARCH 95.12(2004):1183-1190.
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