Local control of β-adrenergic stimulation: Effects on ventricular myocyte electrophysiology and Ca(2+)-transient.
Local control of β-adrenergic stimulation: Effects on ventricular myocyte electrophysiology and Ca(2+)-transient.
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DOI：
10.1016/j.yjmcc.2011.02.007
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发表时间：
2011-05
影响因子：
5
通讯作者：
Rudy Y
中科院分区：
文献类型：
--
作者：
Heijman J;Volders PG;Westra RL;Rudy Y
局部信号结构域和许多相互作用的分子途径和底物有助于β-肾上腺素能刺激（βARS）期间肌细胞的全细胞反应。我们旨在阐明βARS过程中底物及其局部信号环境对犬心外膜心室肌细胞电生理和钙瞬变（CaT）的定量贡献。我们提出了一个计算房室模型的βARS及其电生理效应。该模型的新方面包括局部信号结构域，β1和β2受体亚型的掺入，详细的基于群体的方法来整合βAR和Ca 2 +/钙调蛋白激酶（CaMKII）信号通路及其对影响全细胞电生理学和CaT的广泛底物的影响。PKA和限制性扩散控制局部cAMP水平，并表明不同受体亚型激活特定cAMP结构域允许特异性控制动作电位和CaT特性。此外，该模型预测由于速率依赖性蓄积和Ca 2+循环增加，βARS期间CaMKII活性增加。预测CaMKII抑制、减少区室化和选择性阻断β1AR可减少βARS期间延迟后除极的发生。最后，每个PKA底物的相对贡献，全细胞电生理学进行量化，通过比较模拟和没有磷酸化的每个目标。总之，该模型通过纳入受体亚型、多途径和多靶点磷酸化的详细描述，增强了我们对心室肌细胞中局部βAR信号传导及其全细胞效应的理解;它为病理条件下βARS的进一步研究提供了基础。
Local signaling domains and numerous interacting molecular pathways and substrates contribute to the whole-cell response of myocytes during β-adrenergic stimulation (βARS). We aimed to elucidate the quantitative contribution of substrates and their local signaling environments during βARS to the canine epicardial ventricular myocyte electrophysiology and calcium transient (CaT). We present a computational compartmental model of βARS and its electrophysiological effects. Novel aspects of the model include localized signaling domains, incorporation of β1 and β2 receptor isoforms, a detailed population-based approach to integrate the βAR and Ca2+/Calmodulin kinase (CaMKII) signaling pathways and their effects on a wide range of substrates that affect whole-cell electrophysiology and CaT. The model identifies major roles for phosphodiesterases, adenylyl cyclases, PKA and restricted diffusion in the control of local cAMP levels and shows that activation of specific cAMP domains by different receptor isoforms allows for specific control of action potential and CaT properties. In addition, the model predicts increased CaMKII activity during βARS due to rate-dependent accumulation and increased Ca2+ cycling. CaMKII inhibition, reduced compartmentation, and selective blockade of β1AR are predicted to reduce the occurrence of delayed afterdepolarizations during βARS. Finally, the relative contribution of each PKA substrate to whole-cell electrophysiology is quantified by comparing simulations with and without phosphorylation of each target. In conclusion, this model enhances our understanding of localized βAR signaling and its whole-cell effects in ventricular myocytes by incorporating receptor isoforms, multiple pathways and a detailed representation of multiple-target phosphorylation; it provides a basis for further studies of βARS under pathological conditions.
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影响因子：
20.1
作者：
Nikolaev, Viacheslav O.;Buenemann, Moritz;Engelhardt, Stefan
通讯作者：
Engelhardt, Stefan
影响因子：
56.9
作者：
Nikolaev, Viacheslav O.;Moshkov, Alexey;Gorelik, Julia
通讯作者：
Gorelik, Julia
影响因子：
5
作者：
Calaghan, Sarah;Kozera, Lukasz;White, Ed
通讯作者：
White, Ed
影响因子：
56.9
作者：
De Koninck, P;Schulman, H
通讯作者：
Schulman, H
DOI：
10.1152/ajpheart.01216.2008
发表时间：
2009-04-01
影响因子：
4.8
作者：
Decker, Keith F.;Heijman, Jordi;Rudy, Yoram
通讯作者：
Rudy, Yoram