Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.

Abstract	Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.
Authors	Xander H T Wehrens, Stephan E Lehnart, Steven R Reiken, Shi-Xian Deng, John A Vest, Daniel Cervantes, James Coromilas, Donald W Landry, Andrew R Marks
Journal	Science (New York, N.Y.) (Science) Vol. 304 Issue 5668 Pg. 292-6 (Apr 09 2004) ISSN: 1095-9203 [Electronic] United States
PMID	15073377 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Anti-Arrhythmia Agents Ryanodine Receptor Calcium Release Channel Thiazepines K201 compound Cyclic AMP-Dependent Protein Kinases Sarcoplasmic Reticulum Calcium-Transporting ATPases Tacrolimus Binding Proteins tacrolimus binding protein 1B Calcium-Transporting ATPases Isoproterenol Calcium
Topics	Animals Anti-Arrhythmia Agents (pharmacology, therapeutic use) Calcium (metabolism) Calcium-Transporting ATPases (metabolism) Cell Line Cyclic AMP-Dependent Protein Kinases (metabolism) Death, Sudden, Cardiac (prevention & control) Electric Stimulation Electrocardiography Heart (drug effects, physiology) Humans Isoproterenol (pharmacology) Mice Myocardial Contraction Phosphorylation Physical Exertion Protein Binding Ryanodine Receptor Calcium Release Channel (metabolism) Sarcoplasmic Reticulum (metabolism) Sarcoplasmic Reticulum Calcium-Transporting ATPases Tachycardia, Ventricular (metabolism, prevention & control) Tacrolimus Binding Proteins (deficiency, genetics, metabolism) Thiazepines (pharmacology, therapeutic use)

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