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Computational Modeling of Cyclic Nucleotide Signaling Mechanisms in Cardiac Myocytes

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Microdomains in the Cardiovascular System

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 3))

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Abstract

The balanced signaling between the two cyclic nucleotides (cNs), cAMP and cGMP, in the cN signaling system plays a critical role in regulating cardiac contractility. Many therapeutic agents have been developed to selectively inhibit or stimulate proteins in the cN signaling system in the attempt to manage and treat heart diseases. Nonetheless, it has been challenging to obtain a comprehensive, system-level understanding of the signal transduction mechanisms, in part because of the participation of multiple phosphodiesterases (PDEs) in the common task of cN degradation, the complex interactions between the signaling proteins, and the large number of cN regulated targets in the tightly coupled excitation-contraction (EC) coupling process. Multi-scale, biophysically detailed, and experimentally validated computational models are well suited to dissect the underlying mechanisms in these nonlinear and intertwined reaction networks. By precisely defining and quantifying biochemical reactions involved, data-driven and integrative modeling bridge causal gaps across spatiotemporal scale, from the characteristics of individual molecular components to the collective responses of the entire signaling network. Through predictive modeling and in-depth analysis, these computational models are powerful in providing insights into cellular mechanisms, formulating novel hypothesis, and proposing possible future experiments. This review focuses on the development of mechanistic models, the close interplay between modeling and experimentation, and the identification of opportunities for future modeling research in the cardiac myocyte cN signaling system.

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Acknowledgments

This work was supported by Natural Sciences and Engineering Research Council (NSERC) of Canada scholarships, CGS M-377616-2009 and PGSD3-405041-2011, awarded to C.Y.Z.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD, 21218, USA

    Claire Y. Zhao

  2. Acute Care Solutions, Philips Research North America, 2 Canal Park, 3rd floor, Cambridge, MA, 02141, USA

    Claire Y. Zhao

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Correspondence to Claire Y. Zhao .

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  1. Institute of Experimental Cardiovascular Research, University Medical Center, Hamburg-Eppendorf, Germany

    Viacheslav Nikolaev

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Manuela Zaccolo

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Zhao, C.Y. (2017). Computational Modeling of Cyclic Nucleotide Signaling Mechanisms in Cardiac Myocytes. In: Nikolaev, V., Zaccolo, M. (eds) Microdomains in the Cardiovascular System. Cardiac and Vascular Biology, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-54579-0_10

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