Kerfant Benoit-Gilles, Rose Robert A, Sun Hui, Backx Peter H
Department of Physiology and Medicine, University of Toronto, Heart & Stroke/Richard Lewar Centre, Toronto, Ontario, Canada M5S 3E2.
Trends Cardiovasc Med. 2006 Oct;16(7):250-6. doi: 10.1016/j.tcm.2006.04.006.
Class I phosphoinositide 3-kinases (PI3Ks) are enzymes with both protein and lipid kinase activities that regulate important cellular functions in many tissues. In the heart, subclass IA PI3Ks (mainly PI3Kalpha) regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kgamma, the only member of subclass IB, has been shown to regulate cardiac contractility. We have shown that the loss of PI3Kgamma (PI3Kgamma(-/-) mice) enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum. Specifically, PI3Kgamma(-/-) mice show enhanced sarcoplasmic reticulum Ca(2+) cycling in association with increased cAMP. Surprisingly, L-type Ca(2+) current, a prototypic target of cAMP-dependent protein kinase A phosphorylation, is largely unchanged in PI3Kgamma(-/-) mice. In this article, we discuss the consequences and implications of cAMP compartmentation in cardiomyocytes. We also review the different roles of PI3Kgamma in the heart, particularly as they relate to cardiac contractility, intracellular cAMP levels, and the regulation of beta-adrenergic receptor signaling in physiologic and pathologic states.
I类磷酸肌醇3激酶（PI3Ks）是具有蛋白质和脂质激酶活性的酶，可调节许多组织中的重要细胞功能。在心脏中，IA亚类PI3Ks（主要是PI3Kα）调节细胞生长、凋亡、细胞分裂和细胞大小，而IB亚类的唯一成员PI3Kγ已被证明可调节心脏收缩力。我们已经表明，PI3Kγ缺失（PI3Kγ基因敲除小鼠）通过调节含有肌浆网的亚细胞结构域中的环磷酸腺苷（cAMP）水平来增强心脏兴奋-收缩偶联。具体而言，PI3Kγ基因敲除小鼠表现出与cAMP增加相关的肌浆网Ca2+循环增强。令人惊讶的是，L型Ca2+电流是cAMP依赖性蛋白激酶A磷酸化的典型靶点，在PI3Kγ基因敲除小鼠中基本未发生变化。在本文中，我们讨论了心肌细胞中cAMP区域化的后果和影响。我们还综述了PI3Kγ在心脏中的不同作用，特别是它们与心脏收缩力、细胞内cAMP水平以及生理和病理状态下β-肾上腺素能受体信号调节的关系。
