Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity
Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity
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尽管 CaMKII 活性过度，但抑制物 1 的慢性缺失会降低心脏 RyR2 磷酸化
DOI：
10.1007/s00210-017-1376-1
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
El-Armouche A
中科院分区：
文献类型：
--
作者：
Neef S ;Brammen CAA;Wittköpper K;Heijman Jr;Antos CL;Otte C;Seitz T;Dewenter M;Saadatmand AR;Meyer-Roxlau S;Vettel C;Weber S;Backs J;Hasenfuss G;Dobrev D;Maier LS;El-Armouche A
Inhibitor-1 (I-1) 调节蛋白磷酸酶 1 (PP1) 活性，从而抵消激酶的磷酸化作用。 I-1 在衰竭的心脏中下调并失活，但其作用是有益还是有害仍然存在争议，并且已经提出了相反的治疗策略。 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 的过度活性以及 CaMKII 位点兰尼碱受体 (RyR2) 的过度磷酸化被认为是心力衰竭和心律失常的核心。使用 I-1 缺陷小鼠系以及转染细胞系，我们研究了 I-1 的急性和慢性调节对 CaMKII 活性和 RyR2 磷酸化的影响。我们证明 I-1 通过调节 PP1 活性来急性调节 CaMKII。然而，虽然 I-1 的消除应该限制 CaMKII 的激活，但我们意外地发现，在基因敲除小鼠中，I-1 慢性丧失后，在 β-肾上腺素能应激下，CaMKII 的激活过度。我们发现这是由于 cAMP (EPAC) 激活的交换蛋白的长期上调导致 CaMKII 激活增强，并且使用计算模型验证了 EPAC 表达的增加确实可以解释我们的实验结果。有趣的是，在 RyR2 水平上，PP1 活性的增加超过了 CaMKII 活性的增加，导致 Ser-2814 处的 RyR 磷酸化减少。由于 I-1 丢失时的反调节机制导致 CaMKII 过度激活，这是关于建议的 I-1 抑制治疗的一个重要警告，因为 CaMKII 过度活跃与多种心脏病密切相关。
Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias. Using an I-1-deficient mouse line as well as transfected cell lines, we investigated the effects of acute and chronic modulation of I-1 on CaMKII activity and RyR2 phosphorylation. We demonstrate that I-1 acutely modulates CaMKII by regulating PP1 activity. However, while ablation of I-1 should thus limit CaMKII-activation, we unexpectedly found exaggerated CaMKII-activation under β-adrenergic stress upon chronic loss of I-1 in knockout mice. We unraveled that this is due to chronic upregulation of the exchange protein activated by cAMP (EPAC) leading to augmented CaMKII activation, and using computational modeling validated that an increase in EPAC expression can indeed explain our experimental findings. Interestingly, at the level of RyR2, the increase in PP1 activity more than outweighed the increase in CaMKII activity, resulting in reduced RyR phosphorylation at Ser-2814. Exaggerated CaMKII activation due to counterregulatory mechanisms upon loss of I-1 is an important caveat with respect to suggested therapeutic I-1-inhibition, as CaMKII overactivity has been heavily implicated in several cardiac pathologies.
Epac 在心脏钙信号传导中的作用。
影响因子：
5
作者：
G. Ruiz‐Hurtado;E. Morel;A. Dominguez;A. Llach;F. Lezoualc’h;J. Benitah;A. Gómez
通讯作者：
A. Gómez
影响因子：
5
作者：
Nicolaou, Persoulla;Hajjar, Roger J.;Kranias, Evangelia G.
通讯作者：
Kranias, Evangelia G.
影响因子：
5
作者：
Heijman J;Volders PG;Westra RL;Rudy Y
通讯作者：
Rudy Y