Dysregulated sarcoplasmic reticulum calcium release: potential pharmacological target in cardiac disease.
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.
Györke
Sandor
S
Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States. sandor.gyorke@osumc.edu
Carnes
Cynthia
C
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006331:Heart Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008954:Models, Biological; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium