A Tale of Two Leaks

Abstract

Over the last 2 decades, understanding of the mechanisms that underlie heart failure (HF) has grown enormously. One of the key concepts is that HF is associated with profound alterations in myocardial calcium handling and excitation-contraction coupling. Article see p 970 Most of the calcium that activates contraction comes from the sarcoplasmic reticulum (SR). It leaves the SR through a specialized release channel known as the ryanodine receptor (RyR). The probability that an RyR is open and can therefore allow Ca to leave the SR into the cytoplasm is increased by an increase in the concentration of either cytosolic or SR (luminal) Ca concentration. During the normal heartbeat, sarcolemmal Ca channels open and some of the entering Ca binds to the RyRs, making them open, thereby triggering the release of a much greater amount of Ca from the SR into the cytosol. This Ca release causes a rapid rise of cytosolic Ca to levels that activate the myofilaments and initiate contraction. After termination of release of Ca from the SR (because of closure of RyRs), cytosolic Ca levels decline rapidly and relaxation occurs. Ca is rapidly removed from the cytosol by 2 major systems: the sarcoendoplasmic reticulum Ca ATPase and the sarcolemmal sodium/calcium exchanger. Sarcoendoplasmic reticulum Ca ATPase pumps Ca back into the SR, whereas sarcolemmal sodium/calcium exchanger pumps 1 Ca2+ out in exchange for the influx of 3 Na+ ions into the cell. This rapid cycle of Ca release and reuptake is known as the systolic Ca transient, and it is one of the main factors that control force of contraction in the heart. It is worth emphasizing that the normal Ca transient depends on the RyRs being virtually closed in diastole, opening very briefly to produce the systolic increase of Ca, and then closing to allow …