Abstract
Excitation-contraction coupling links excitation of the sarcolemmal surface membrane to mechanical contraction. In the heart this link is established via a Ca(2+)-induced Ca(2+) release process, which, following sarcolemmal depolarisation, prompts Ca(2+) release from the sarcoplasmic reticulum (SR) though the ryanodine receptor (RyR2). This substantially raises the cytoplasmic Ca(2+) concentration to trigger systole. In diastole, Ca(2+) is removed from the cytoplasm, primarily via the sarcoplasmic-endoplasmic reticulum Ca(2+)-dependent ATPase (SERCA) pump on the SR membrane, returning Ca(2+) to the SR store. Ca(2+) movement across the SR is thus fundamental to the systole/diastole cycle and plays an essential role in maintaining cardiac contractile function. Altered SR Ca(2+) homeostasis (due to disrupted Ca(2+) 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 Ca(2+) 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.