Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.
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.
Wehrens
Xander H T
XH
Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Lehnart
Stephan E
SE
Reiken
Steven R
SR
Deng
Shi-Xian
SX
Vest
John A
JA
Cervantes
Daniel
D
Coromilas
James
J
Landry
Donald W
DW
Marks
Andrew R
AR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004558:Electric Stimulation; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction; D010766:Phosphorylation; D005082:Physical Exertion; D011485:Protein Binding; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000517:prevention & control*; D022021:Tacrolimus Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013841:Thiazepines / Q000494:pharmacology* / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound; D017868:Cyclic AMP-Dependent Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium