The Cardiac Sarcoplasmic Reticulum

Abstract

Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is the cornerstone of cardiac excitation-contraction coupling and Ca2+ signaling.1,2 However, as an amplification mechanism exhibiting a high degree of positive feed-back, it has to be kept in check by inhibitory systems to prevent spontaneous oscillatory Ca2+ releases which could possibly trigger cardiac arrhythmias. Local control theory provides us with an initial frame-work to understand how this could be accomplished.3 Mutually independent Ca2+ signaling events (Ca2+ sparks4) generate the necessary amplification locally without spreading to neighboring Ca2+ release sites, whereas the normal signal transduction from L-type Ca2+ channels to the SR occurs within the microdomain of the dyadic cleft, well isolated from the bulk of the cytosol. Uncoupling between neighboring Ca2+ spark sites thus ensures the reliability of the CICR system and occurs by virtue of steep concentration gradients away from the microdomain of Ca2+ release, and by means of the relative insensitivity of the SR Ca2+ release channels (ryanodine receptors [RyRs]) toward cytosolic Ca2+ triggers.5 This uncoupling by local control also underlies the observation that Ca2+ sparks occurring spontaneously remain localized and do not initiate a chain reaction of Ca2+ sparks traveling along the entire myocyte as a Ca2+ wave. However, this system can also become unstable and CICR is capable to override local control and to trigger oscillatory Ca2+ signals in cardiomyocytes, particularly under pathophysiological conditions. Waves of contractions traveling along isolated cardiomyocytes have been discovered and the underlying Ca2+ …