Mechanisms of SR calcium release in healthy and failing human hearts.

Normal heart contraction and rhythm relies on the proper flow of calcium ions (Ca) into cardiac cells and between their intracellular organelles, and any disruption can lead to arrhythmia and sudden cardiac death. Electrical excitation of the surface membrane activates voltage-dependent L-type Ca channels to open and allow Ca to enter the cytoplasm. The subsequent increase in cytoplasmic Ca concentration activates calcium release channels (RyR2) located at specialised Ca release sites in the sarcoplasmic reticulum (SR), which serves as an intracellular Ca store. Animal models have provided valuable insights into how intracellular Ca transport mechanisms are altered in human heart failure. The aim of this review is to examine how Ca release sites are remodelled in heart failure and how this affects intracellular Ca transport with an emphasis on Ca release mechanisms in the SR. Current knowledge on how heart failure alters the regulation of RyR2 by Ca and Mg and how these mechanisms control the activity of RyR2 in the confines of the Ca release sites is reviewed.