Dynamic local changes in sarcoplasmic reticulum calcium: Physiological and pathophysiological roles

Abstract 

Evidence obtained in recent years indicates that, in cardiac myocytes, release of Ca²⁺ from the sarcoplasmic reticulum (SR) is regulated by changes in the concentration of Ca²⁺ within the SR. In this review, we summarize recent advances in our understanding of this regulatory role, with a particular emphasis on dynamic and local changes in SR [Ca²⁺]. We focus on five important questions that are to some extent unresolved and controversial. These questions concern: (1) the importance of SR [Ca²⁺] depletion in the termination of Ca²⁺ release; (2) the quantitative extent of depletion during local release events such as Ca²⁺ sparks; (3) the influence of SR [Ca²⁺] refilling on release refractoriness and the propensity for pathological Ca²⁺ release; (4) dynamic changes in SR [Ca²⁺] during propagating Ca²⁺ waves; and (5) the speed of Ca²⁺ diffusion within the SR. With each issue, we discuss data supporting alternative viewpoints, and we identify fundamental questions that are being actively investigated. We conclude with a discussion of experimental and computational advances that will help to resolve controversies. This article is part of a special issue entitled "Local Signaling in Myocytes."

Keywords: Ca²⁺ spark, Ca²⁺ wave, Ca²⁺ transient, Arrhythmia, Triggered activity, Ventricular myocyte, Mathematical modeling