Regulation and dysregulation of cardiac ryanodine receptor (RyR2) open probability during diastole in health and disease

Each contractile cycle in the heart, each heartbeat, requires an efflux of Ca2+ from the intracellular sarcoplasmic reticulum (SR) Ca2+ store through cardiac ryanodine receptor (RyR2) Ca2+ release channels. This release is followed by the reuptake of Ca2+ into the SR by the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) Ca2+ pump. The Ca2+ cycle is initiated by action potential depolarization, which allows Ca2+ entry into the cardiac myoctye from extracellular sources through L-type Ca2+ channels in the surface/transverse tubule membrane. The Ca2+ binds to Ca2+ activation sites located on the very large cytoplasmic domain of RyR2 and produces a massive increase in the open probability of this ligand-gated ion channel in the process of Ca2+-induced Ca2+ release. Ca2+ flows through the open ion channel, down its concentration gradient, from the lumen of the SR into the cytoplasm where it binds to troponin C and activates the contractile machinery. After action potential repolarization, the myocardium relaxes as cytoplasmic Ca2+ falls. This is a net effect of a decline in the open probability of the RyR2 to very low levels, and Ca2+ is pumped back into the SR by SERCA, with a small amount of Ca2+ extrusion from the cell through the surface membrane Na+–Ca2+ exchanger (NCX). Ca2+ enters the myocyte through NCX during the action potential depolarization and is extruded through NCX when the membrane potential is repolarized. Ca2+ movement through NCX contributes minimally to changes in cytoplasmic Ca2+ in normal muscle but can become dominant during heart failure. The Ca2+ cycle is generally divided into two periods: systole, when the ventricular myocardium contracts and ejects the contents of the ventricle, and diastole, where the ventricular muscle relaxes and the chamber refills. The systolic period encompasses surface depolarization and repolarization, Ca2+ entry through the L-type Ca2+ channels, release from the SR, and influx through NCX. During diastole, the membrane potential remains repolarized, and Ca2+ is taken back into the SR to be available for the next release phase and is extruded through NCX