Journal
PHARMACOLOGY & THERAPEUTICS
Volume 119, Issue 3, Pages 340-354Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2008.06.002
Keywords
ryanodine receptor; calcium release; calsequestrin; junctin; triadin; cardiomyopathy; arrhythmias
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Funding
- NHLBI NIH HHS [R01 HL074045, R01 HL074045-07] Funding Source: Medline
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In the heart, Ca2+ released from the intracellular Ca2+ storage site, the sarcoplasmic reticulum (SR), is the principal determinant of cardiac contractility. SR Ca2+ 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 UN). Acquired and genetic defects in the components of the release channel complex result in a spectrum of abnormal Ca2+ release phenotypes ranging from arrhythmogenic spontaneous Ca2+ releases and Ca2+ alternans to the uniformly diminished systolic Ca2+ release characteristic of heart failure. In this article, we will present an overview of the structure and molecular components of the SR and Ca2+ release machinery and its modulation by different intracellular factors, such as Ca2+ levels inside the SR as well as phosphorylation and redox modification of RyR2s. We will also discuss the relationships between abnormal SIR Ca2+ release and various cardiac disease phenotypes, including, arrhythmias and heart failure, and consider SR Ca2+ release as a potential therapeutic target. (C) 2008 Published by Elsevier Inc.
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