Synergy between CaMKII Substrates and β-Adrenergic Signaling in Regulation of Cardiac Myocyte Ca2+ Handling
Synergy between CaMKII Substrates and β-Adrenergic Signaling in Regulation of Cardiac Myocyte Ca2+ Handling
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DOI：
10.1016/j.bpj.2010.08.016
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发表时间：
2010-10-06
影响因子：
3.4
通讯作者：
Saucerman, Jeffrey J.
中科院分区：
文献类型：
--
作者：
Soltis, Anthony R.;Saucerman, Jeffrey J.
心肌兴奋-收缩偶联是一个高度协调的过程，受包括钙/钙调蛋白依赖的蛋白激酶II(CaMKII)和蛋白激酶A(PKA)在内的蛋白激酶信号通路的调控。CaMKII的表达和活性增加(在心力衰竭期间发生)破坏EC偶联的稳定性，并可能导致心源性猝死。为了更好地了解心脏CaMKII功能的机制，我们将关键的钙处理靶标的CaMKII依赖的动态调节与先前验证的心脏EC偶联、CaMKII的钙/钙调蛋白依赖的激活以及PKA的β-肾上腺素能激活的模型相结合。根据兔心肌细胞的CaMKII过表达数据，模型预测得到了验证。该模型展示了CaMKII过表达过程中钙离子处理的总体变化是如何通过单个CaMKII底物之间的相互作用来解释的。在β-肾上腺素能刺激过程中，CaMKII和PKA的活性可能协同促进变力反应，并参与CaMKII-钙-CaMKII反馈回路。CaMKII调节早期频率依赖性的松弛加速和EC偶联增益(这高度依赖于肌浆网钙负荷)。此外，该模型还发现CaMKII依赖的ryanodine受体过度磷酸化是导致心律失常的触发因素。综上所述，我们建立了CaMKII和PKA信号的详细计算模型。这为他们对正常和病理性的钙离子处理的调节提供了独特的见解。
Cardiac excitation-contraction coupling is a highly coordinated process that is controlled by protein kinase signaling pathways, including Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA). Increased CaMKII expression and activity (as occurs during heart failure) destabilizes EC coupling and may lead to sudden cardiac death. To better understand mechanisms of cardiac CaMKII function, we integrated dynamic CaMKII-dependent regulation of key Ca2+ handling targets with previously validated models of cardiac EC coupling, Ca2+/calmodulin-dependent activation of CaMKII, and beta-adrenergic activation of PKA. Model predictions are validated against CaMKII-overexpression data from rabbit ventricular myocytes. The model demonstrates how overall changes to Ca2+ handling during CaMKII overexpression are explained by interactions between individual CaMKII substrates. CaMKII and PKA activities during beta-adrenergic stimulation may synergistically facilitate inotropic responses and contribute to a CaMKII-Ca2+-CaMKII feedback loop. CaMKII regulated early frequency-dependent acceleration of relaxation and EC coupling gain (which was highly sarcoplasmic reticulum Ca2+ load-dependent). Additionally, the model identifies CaMKII-dependent ryanodine receptor hyperphosphorylation as a proarrhythmogenic trigger. In summary, we developed a detailed computational model of CaMKII and PKA signaling. in cardiac myocytes that provides unique insights into their regulation of normal and pathological Ca2+ handling.