Simula Research Laboratory, Department of Computational Physiology, PO Box 134, 1325 Lysaker, Norway.
University of California San Diego, Department of Mechanical and Aerospace Engineering, 9500 Gilman Drive MC 0411, La Jolla, CA 92093, United States of America.
J Mol Cell Cardiol. 2021 May;154:32-40. doi: 10.1016/j.yjmcc.2021.01.008. Epub 2021 Feb 4.
The cAMP/PKA pathway is a fundamental regulator of excitation-contraction coupling in cardiomyocytes. Activation of cAMP has a variety of downstream effects on cardiac function including enhanced contraction, accelerated relaxation, adaptive stress response, mitochondrial regulation, and gene transcription. Experimental advances have shed light on the compartmentation of cAMP and PKA, which allow for control over the varied targets of these second messengers and is disrupted in heart failure conditions. Computational modeling is an important tool for understanding the spatial and temporal complexities of this system. In this review article, we outline the advances in computational modeling that have allowed for deeper understanding of cAMP/PKA dynamics in the cardiomyocyte in health and disease, and explore new modeling frameworks that may bring us closer to a more complete understanding of this system. We outline various compartmental and spatial signaling models that have been used to understand how β-adrenergic signaling pathways function in a variety of simulation conditions. We also discuss newer subcellular models of cardiovascular function that may be used as templates for the next phase of computational study of cAMP and PKA in the heart, and outline open challenges which are important to consider in future models.
cAMP/PKA 通路是心肌细胞兴奋-收缩偶联的基本调节因子。cAMP 的激活对心脏功能有多种下游影响，包括增强收缩、加速松弛、适应应激反应、线粒体调节和基因转录。实验进展揭示了 cAMP 和 PKA 的区室化，这允许对这些第二信使的各种靶标进行控制，而在心力衰竭情况下会受到破坏。计算建模是理解该系统时空复杂性的重要工具。在这篇综述文章中，我们概述了计算建模的进展，这些进展使我们能够更深入地了解健康和疾病状态中心肌细胞中 cAMP/PKA 的动力学，并探讨了可能使我们更接近对该系统更完整理解的新建模框架。我们概述了各种用于理解β-肾上腺素能信号通路在各种模拟条件下如何发挥作用的区室化和空间信号模型。我们还讨论了可能作为心脏中 cAMP 和 PKA 下一阶段计算研究模板的新的亚细胞心血管功能模型，并概述了未来模型中需要考虑的重要开放性挑战。
