Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte

<jats:p>Calcium (Ca<jats:sup>2+</jats:sup>) plays many important regulatory roles in cardiac muscle cells. In the initial phase of the action potential, influx of Ca<jats:sup>2+</jats:sup> through sarcolemmal voltage‐gated L‐type Ca<jats:sup>2+</jats:sup> channels (<jats:styled-content style="fixed-case">LCCs</jats:styled-content>) acts as a feed‐forward signal that triggers a large release of Ca<jats:sup>2+</jats:sup> from the junctional sarcoplasmic reticulum (SR). This Ca<jats:sup>2+</jats:sup> drives heart muscle contraction and pumping of blood in a process known as excitation–contraction coupling (<jats:styled-content style="fixed-case">ECC</jats:styled-content>). Triggered and released Ca<jats:sup>2+</jats:sup> also feed back to inactivate <jats:styled-content style="fixed-case">LCCs</jats:styled-content>, attenuating the triggered Ca<jats:sup>2+</jats:sup> signal once release has been achieved. The process of <jats:styled-content style="fixed-case">ECC</jats:styled-content> consumes large amounts of <jats:styled-content style="fixed-case">ATP</jats:styled-content>. It is now clear that in a process known as excitation–energetics coupling, Ca<jats:sup>2+</jats:sup> signals exert beat‐to‐beat regulation of mitochondrial <jats:styled-content style="fixed-case">ATP</jats:styled-content> production that closely couples energy production with demand. This occurs through transport of Ca<jats:sup>2+</jats:sup> into mitochondria, where it regulates enzymes of the tricarboxylic acid cycle. In excitation–signaling coupling, Ca<jats:sup>2+</jats:sup> activates a number of signaling pathways in a feed‐forward manner. Through effects on their target proteins, these interconnected pathways regulate Ca<jats:sup>2+</jats:sup> signals in complex ways to control electrical excitability and contractility of heart muscle. In a process known as excitation–transcription coupling, Ca<jats:sup>2+</jats:sup> acting primarily through signal transduction pathways also regulates the process of gene transcription. Because of these diverse and complex roles, experimentally based mechanistic computational models are proving to be very useful for understanding Ca<jats:sup>2+</jats:sup> signaling in the cardiac myocyte. <jats:italic>WIREs Syst Biol Med</jats:italic> 2016, 8:37–67. doi: 10.1002/wsbm.1322</jats:p><jats:p>This article is categorized under: <jats:list list-type="explicit-label"> <jats:list-item><jats:p>Biological Mechanisms > Cell Signaling</jats:p></jats:list-item> <jats:list-item><jats:p>Analytical and Computational Methods > Computational Methods</jats:p></jats:list-item> <jats:list-item><jats:p>Models of Systems Properties and Processes > Mechanistic Models</jats:p></jats:list-item> </jats:list></jats:p>