通过 p110γ 的 PKA 锚定功能整合心脏 PIP3 和 cAMP 信号。
Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ.
机构信息
Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy.
出版信息
Mol Cell. 2011 Apr 8;42(1):84-95. doi: 10.1016/j.molcel.2011.01.030.
Abstract
Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110γ participates in these processes by sustaining β-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110γ anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production. This provides local feedback control of PIP(3) and cAMP signaling events. In congestive heart failure, p110γ is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in β-adrenergic receptor density. Pharmacological inhibition of p110γ normalizes β-adrenergic receptor density and improves contractility in failing hearts.
摘要
肾上腺素能刺激心脏会参与 cAMP 和磷酯酰肌醇第二信使信号级联反应。心脏磷酯酰肌醇 3-激酶 p110γ 通过其催化功能维持β-肾上腺素能受体内化，并通过未知的激酶非依赖性机制控制磷酸二酯酶 3B (PDE3B) 活性，从而参与这些过程。我们发现 p110γ 通过其 N 端区域的一个位点锚定蛋白激酶 A (PKA)。锚定的 PKA 激活 PDE3B 以增强 cAMP 降解，并磷酸化 p110γ 以抑制 PIP(3)的产生。这为 PIP(3)和 cAMP 信号事件提供了局部反馈控制。在充血性心力衰竭中，p110γ 上调并逃避 PKA 介导的抑制，导致β-肾上腺素能受体密度降低。p110γ 的药理学抑制可使β-肾上腺素能受体密度正常化，并改善衰竭心脏的收缩性。
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