Regulation of Cardiac PKA Signaling by cAMP and Oxidants.
Regulation of Cardiac PKA Signaling by cAMP and Oxidants.
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DOI：
10.3390/antiox10050663
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发表时间：
2021-04-24
期刊：
影响因子：
--
通讯作者：
Diering S
中科院分区：
文献类型：
--
作者：
Cuello F;Herberg FW;Stathopoulou K;Henning P;Diering S
病理学，如癌症、炎症和心脏病通常与被称为氧化应激的活性氧的长期增加的产生和释放有关。因此，蛋白质氧化传递蛋白质功能障碍并有助于疾病进展。重要的是，通过全身性抗氧化剂治疗来抑制氧化剂的试验失败了。这一观察结果支持了氧化剂是诱导靶蛋白氧化翻译后修饰的不可或缺的生理信号分子的观点。在心肌细胞中，心肌收缩力的主要驱动因素是β-肾上腺素受体信号级联的激活，导致细胞cAMP产生增加及其主要效应物cAMP依赖性蛋白激酶（PKA）的激活。PKA介导的参与兴奋-收缩偶联的底物蛋白的磷酸化是观察到的正性肌力作用和负性肌力作用的原因。PKA作用被细胞蛋白磷酸酶（PP）抵消，其使底物蛋白去磷酸化，从而允许PKA信号传导的终止。激酶和磷酸酶都是氧化还原敏感的，并且对关键半胱氨酸残基上的氧化敏感。因此，氧化的调节PKA和PP亚基被认为是调节亚细胞激酶和磷酸酶的定位，而内二硫键形成的催化亚基的催化活性产生负面影响，直接影响底物（去）磷酸化和心脏收缩功能。这篇综述文章试图将目前的看法的功能相关的调节心脏收缩力的经典cAMP依赖性信号与氧化修饰的贡献。
Pathologies, such as cancer, inflammatory and cardiac diseases are commonly associated with long-term increased production and release of reactive oxygen species referred to as oxidative stress. Thereby, protein oxidation conveys protein dysfunction and contributes to disease progression. Importantly, trials to scavenge oxidants by systemic antioxidant therapy failed. This observation supports the notion that oxidants are indispensable physiological signaling molecules that induce oxidative post-translational modifications in target proteins. In cardiac myocytes, the main driver of cardiac contractility is the activation of the β-adrenoceptor-signaling cascade leading to increased cellular cAMP production and activation of its main effector, the cAMP-dependent protein kinase (PKA). PKA-mediated phosphorylation of substrate proteins that are involved in excitation-contraction coupling are responsible for the observed positive inotropic and lusitropic effects. PKA-actions are counteracted by cellular protein phosphatases (PP) that dephosphorylate substrate proteins and thus allow the termination of PKA-signaling. Both, kinase and phosphatase are redox-sensitive and susceptible to oxidation on critical cysteine residues. Thereby, oxidation of the regulatory PKA and PP subunits is considered to regulate subcellular kinase and phosphatase localization, while intradisulfide formation of the catalytic subunits negatively impacts on catalytic activity with direct consequences on substrate (de)phosphorylation and cardiac contractile function. This review article attempts to incorporate the current perception of the functionally relevant regulation of cardiac contractility by classical cAMP-dependent signaling with the contribution of oxidant modification.
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影响因子：
7.3
作者：
Chen, Mark J.;Dixon, Jack E.;Manning, Gerard
通讯作者：
Manning, Gerard
影响因子：
16.2
作者：
CADD, G;MCKNIGHT, GS
通讯作者：
MCKNIGHT, GS
DOI：
10.1073/pnas.85.12.4252
发表时间：
1988-06-01
影响因子：
11.1
作者：
ARINO, J;CHEE, WW;JOHNSON, GL
通讯作者：
JOHNSON, GL
影响因子：
--
作者：
Aye, Thin Thin;Scholten, Arjen;Heck, Albert J. R.
通讯作者：
Heck, Albert J. R.
Netrin-1在胰腺癌中抑制MEK/ERK途径和ITGB4。
影响因子：
--
作者：
An XZ;Zhao ZG;Luo YX;Zhang R;Tang XQ;Hao D;Zhao X;Lv X;Liu D
通讯作者：
Liu D