Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease

The cardiac ryanodine receptor (RyR2) is the sarcoplasmic reticulum (SR) Ca2+ release channel which is responsible for generation of the cytosolic Ca2+ transient required for activation of cardiac contraction. RyR2 functional activity is governed by changes in [Ca2+] on both the cytosolic and luminal phase of the RyR2 channel. Activation of RyR2 by cytosolic Ca2+ results in Ca2+-induced Ca2+ release (CICR) from the SR. The decline in luminal [Ca2+] following release contributes to termination of CICR and Ca2+ signalling refractoriness through the process of luminal Ca2+-dependent deactivation of RyR2s. The control of RyR2s by luminal Ca2+ involves coordinated interaction of the channel with several SR proteins, including the Ca2+-binding protein calsequestrin (CASQ2), and the integral proteins triadin 1 (TRD) and junctin (JCN). CASQ2 in addition to serving as a Ca2+ Storage site and a luminal Ca2+ buffer modulates RyR2 function more directly as a putative luminal Ca2+ sensor. TRD and JCN, stimulatory by themselves, mediate the interactions between CASQ2 and RyR2. Acquired and genetic defects in proteins of this junctional Ca2+ signalling complex lead to disease states such as cardiac arrhythmia and heart failure by impairing luminal Ca2+ regulation of RyR2.