Integrated Ca2+ management in cardiac myocytes.

Cardiac myocyte excitation-contraction coupling is complex. There are many systems involved that interact to form varied, but well-tuned, effects that are essential to contractile regulation. Nearly all of these systems are Ca-dependent, and Ca homeostasis within the myocyte is carefully controlled. Contractile activation results from Ca entry via Ca current, and Ca release from the sarcoplasmic reticulum (SR). Ca extrusion from the cytosol is controlled by Ca transport by (1) the Na-Ca exchanger, (2) the SR Ca-pump (which is balanced by a Ca leak out of the SR), and (3) slower systems (including Ca transport by mitochondria and the sarcolemmal Ca-pump). These systems interact to regulate the amount of Ca within the cell at rest, most of which is stored within the SR. The amount of Ca released from the SR depends nonlinearly upon SR [Ca], specifically the free SR [Ca] ([Ca](SR)). The relationship is particularly steep at high [Ca](SR), where spontaneous release can take place, resulting in electrical arrhythmias. In many models of heart failure, SR [Ca] is reduced, which may cause decreased Ca release and contractile dysfunction. In summary, the varied processes responsible for Ca regulation within the myocyte are critical to normal heart function, and disruption of the normal operation of these proteins can cause widely varied pathological effects, in large part due to dysfunctional Ca handling.