Abstract
Excitation-contraction coupling links excitation of the sarcolemmal surface membrane to mechanical contraction. In the heart this link is established via a Ca2+-induced Ca2+ release process, which, following sarcolemmal depolarisation, prompts Ca2+ release from the sarcoplasmic reticulum (SR) though the ryanodine receptor (RyR2). This substantially raises the cytoplasmic Ca2+ concentration to trigger systole. In diastole, Ca2+ is removed from the cytoplasm, primarily via the sarcoplasmic-endoplasmic reticulum Ca2+-dependent ATPase (SERCA) pump on the SR membrane, returning Ca2+ to the SR store. Ca2+ movement across the SR is thus fundamental to the systole/diastole cycle and plays an essential role in maintaining cardiac contractile function. Altered SR Ca2+ homeostasis (due to disrupted Ca2+ release, storage, and reuptake pathways) is a central tenet of heart failure and contributes to depressed contractility, impaired relaxation, and propensity to arrhythmia. This review will focus on the molecular mechanisms that underlie asynchronous Ca2+ cycling around the SR in the failing heart. Further, this review will illustrate that the combined effects of expression changes and disruptions to RyR2 and SERCA2a regulatory pathways are critical to the pathogenesis of heart failure.
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References
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Amanda Denniss is supported by a Research Training Program stipend. Alexander Dashwood is supported by a University of Queensland Graduate School Scholarship. Nicole Beard and Peter Molenaar are supported funded by a National Heart Foundation Vanguard Grant.
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Denniss, A.L., Dashwood, A.M., Molenaar, P. et al. Sarcoplasmic reticulum calcium mishandling: central tenet in heart failure?. Biophys Rev 12, 865–878 (2020). https://doi.org/10.1007/s12551-020-00736-y
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DOI: https://doi.org/10.1007/s12551-020-00736-y