Dysregulated sarcoplasmic reticulum calcium release: Potential pharmacological target in cardiac disease

Abstract

In the heart, Ca 2+ released from the intracellular Ca 2+ storage site, the sarcoplasmic reticulum (SR), is the principal determinant of cardiac contractility. SR Ca 2+ release is controlled by dedicated molecular machinery, composed of the cardiac ryanodine receptor (RyR2) and a number of accessory proteins, including FKBP12.6, calsequestrin (CASQ2), triadin (TRD) and junctin (JN). Acquired and genetic defects in the components of the release channel complex result in a spectrum of abnormal Ca 2+ release phenotypes ranging from arrhythmogenic spontaneous Ca 2+ releases and Ca 2+ alternans to the uniformly diminished systolic Ca 2+ release characteristic of heart failure. In this article, we will present an overview of the structure and molecular components of the SR and Ca 2+ release machinery and its modulation by different intracellular factors, such as Ca 2+ levels inside the SR as well as phosphorylation and redox modification of RyR2s.We will also discuss the relationships between abnormal SR Ca 2+ release and various cardiac disease phenotypes, including, arrhythmias and heart failure, and consider SR Ca 2+ release as a potential therapeutic target.

Decreased RyR2 refractoriness determines myocardial synchronization of aberrant Ca 2+ release in a genetic model of arrhythmia

“…In various disease settings, aberrant diastolic Ca 2+ release (DCR) from the SR gives rise to arrhythmic ectopic activity (10)(11)(12)(13)(14). The pathologic link between diastolic dysregulated Ca 2+ release and arrhythmia is particularly evident in catecholaminergic polymorphic ventricular tachycardia (CPVT), a familial form of arrhythmia caused by mutations in the components of the RyR2 complex, including RyR2 and CASQ2 (15,16).…”

Combination Therapy With Beta Blocker and Inotrope in Decompensated Heart Failure: A Clinical Observation

“…21 Moreover, these changes may result in improvements in inotropy and lusitropy without increasing arrhythmogenesis and cardiotoxicity. [22][23][24][25] Acute BB therapy inhibits Ca 2+ leakage from failing RyR2 even at a low dose, and addition to milrinone suppresses milrinone-induced Ca 2+ leakage from failing RyR2 , leading to greater improvement in cardiomyocyte function in dogs. 26 In the presence of BB, the harmful sustained β-receptor pathway signaling associated with HF, mediated through cAMP-independent G-α-stimulating protein coupling of calcium channels, 27 is eliminated as well.…”

Targeting the Arrhythmogenic Substrate in Atrial Fibrillation: Focus on Structural Remodeling

“…Because the toxicity of some amyloid peptides is mediated via ROS pathways [147], one may speculate that atrial amyloidosis increases oxidative damage favoring AF. Notably, atrial redox state influenced activity of several ion channels, including the L-type calcium channel, sodium channel, the transient outward potassium current, sarcoplasmic reticulum Ca ++ -ATPase (SERCA) and the ryanodine receptor (Ryr2), thus affecting the intracellular calcium handling that ultimately may trigger arrhythmia [148]. ROS activate redox-sensitive transcription factors such as nuclear factor kB (NF-kB), which in turn promotes gene transcription, including tumor necrosis factor (TNF-α), the adhesion molecules endothelial leukocyte adhesion molecule (ELAM)-1 and intercellular adhesion molecule (ICAM)-1 [149].…”

“…Direct (electrophysiolocial) and indirect mechanisms have been proposed to explain the antyarrhythmic effects of RAAS blockade [236]. Because calcium handling abnormalities are recognized to be arrhythmogenic [148,242], intracellular calcium cycling is a relevant target of RAAS activation. As previously discussed, activation of AT-1 receptors increases phosphorylation of L-type calcium currents, thereby contributing to the positive inotropic effect of AngII.…”