Modeling β-adrenergic control of cardiac myocyte contractility in silico
Modeling β-adrenergic control of cardiac myocyte contractility in silico
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DOI：
10.1074/jbc.m308362200
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发表时间：
2003-11-28
影响因子：
4.8
通讯作者：
McCulloch, AD
中科院分区：
文献类型：
--
作者：
Saucerman, JJ;Brunton, LL;McCulloch, AD
β-肾上腺素能信号通路通过前馈和反馈机制的组合调节心肌细胞收缩性。我们使用系统分析，以调查如何组件和拓扑结构的信号网络允许神经激素控制兴奋收缩耦合在大鼠心室肌细胞。制定了一个动力学模型整合β-肾上腺素能信号与兴奋-收缩耦合，每个子系统进行了验证与独立的生化和生理测量。模型分析用于定量研究特定分子扰动的影响。3-在模型中，腺苷酸环化酶的倍数过表达使环AMP合成速率比β 1肾上腺素能受体的同等过表达高85%，并且操纵G（s）α对腺苷酸环化酶的亲和力是环AMP产生的更有效调节剂。该模型预测，在最大受体激活下，可能会刺激不到40%的腺苷酸环化酶分子，并建议了一种实验方案来验证这一预测。该模型还预测，内源性热稳定蛋白激酶抑制剂可以提高基础环AMP缓冲68%，并增加蛋白激酶A活化的表观希尔系数从1.0到2.0。最后，发现L-型钙通道和受磷蛋白的磷酸化足以预测肌细胞收缩力的主要变化，包括收缩期钙增加2.6倍（变力性）和钙半松弛时间减少28%（lustropy）。通过进行系统分析，β-肾上腺素能信号网络中分子扰动的后果可以在整合细胞生理学的背景下理解。
The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta(1)-adrenergic receptor, and manipulating the affinity of G(s)alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6 x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.