Sarcoplasmic Reticulum Ca Homeostasis and Heart Failure

Heart function vitally relies on precisely controlled intracellular Ca homeostasis during each cardiac cycle. Abnormalities in Ca regulation cause contractile dysfunction and arrhythmias under different pathological conditions including heart failure (HF). Playing a particularly important role in heart contraction is the sarcoplasmic reticulum (SR). In adult ventricular myocytes, the SR forms a highly interconnected network of tubules (free SR) and cisterns (junctional SR). Although the SR occupies only 2–4 % of the total cell volume [1], it provides the major portion of Ca that initiates contraction. The ability of the SR to accumulate large amounts of Ca is ensured by the SR-specific low affinity and high capacity Ca binding protein calsequestrin (CASQ) [2]. Ca is released from the SR as a result of activation of specialized Ca channels— ryanodine receptors (RyRs; type 2 isoform). These Ca channels are activated by a relatively small inward Ca current via L-type Ca channels (LTCCs) during an action potential (AP). This mechanism which mediates cardiac excitation–contraction coupling (ECC) is known as Ca-induced Ca release (CICR) [3]. In ventricular myocytes CICR occurs at specialized subcellular microdomains where a T-tubule of the sarcolemma is proximal to a junction of the SR forming a dyad (Fig. 1a). Dyadic junctional SR membrane contains clusters of ~100 RyRs [4] that are strategically aligned with LTCCs by junctophilins [5] which ensure that the dyadic cleft is narrow enough (~10–30 nm) to promote efficient signaling from the T-tubule network to the SR. Each of these microdomains constitutes a SR Ca