Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2

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

doi:10.1126/science.1094301

Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2

Science. 2004 Apr 9;304(5668):292-6. doi: 10.1126/science.1094301.

Authors

Xander H T Wehrens¹, Stephan E Lehnart, Steven R Reiken, Shi-Xian Deng, John A Vest, Daniel Cervantes, James Coromilas, Donald W Landry, Andrew R Marks

Affiliation

¹ Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

PMID: 15073377
DOI: 10.1126/science.1094301

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Anti-Arrhythmia Agents / pharmacology*
Anti-Arrhythmia Agents / 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*
Heart / 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
Tachycardia, Ventricular / prevention & control*
Tacrolimus Binding Proteins / deficiency
Tacrolimus Binding Proteins / genetics
Tacrolimus Binding Proteins / metabolism*
Thiazepines / pharmacology*
Thiazepines / therapeutic use

Substances

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