Publication Date:
2004-04-10
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wehrens, Xander H T -- Lehnart, Stephan E -- Reiken, Steven R -- Deng, Shi-Xian -- Vest, John A -- Cervantes, Daniel -- Coromilas, James -- Landry, Donald W -- Marks, Andrew R -- New York, N.Y. -- Science. 2004 Apr 9;304(5668):292-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15073377" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
