Journal article
FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death
Cell, Vol.113(7), pp.829-840
06/27/2003
DOI: 10.1016/S0092-8674(03)00434-3
PMID: 12837242
Abstract
Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca2+ release and cardiac contractility. FKBP12.6−/− mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that “leaky” RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.
Details
- Title: Subtitle
- FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death
- Creators
- Xander H.T Wehrens - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USAStephan E Lehnart - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USAFannie Huang - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USAJohn A Vest - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USASteven R Reiken - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USAPeter J Mohler - Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710 USAJie Sun - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USASilvia Guatimosim - Medical Biotechnology Center, University of Maryland Biotechnology Institute, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201 USALong-Sheng Song - Medical Biotechnology Center, University of Maryland Biotechnology Institute, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201 USANora Rosemblit - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USAJeanine M D'Armiento - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USACarlo Napolitano - Molecular Cardiology, IRCCS Fondazione S. Maugeri, University of Pavia, Via Ferrata 8, 27100 Pavia, ItalyMirella Memmi - Molecular Cardiology, IRCCS Fondazione S. Maugeri, University of Pavia, Via Ferrata 8, 27100 Pavia, ItalySilvia G Priori - Molecular Cardiology, IRCCS Fondazione S. Maugeri, University of Pavia, Via Ferrata 8, 27100 Pavia, ItalyW.J Lederer - Medical Biotechnology Center, University of Maryland Biotechnology Institute, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201 USAAndrew R Marks - Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 USA
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.113(7), pp.829-840
- Publisher
- Elsevier Inc
- DOI
- 10.1016/S0092-8674(03)00434-3
- PMID
- 12837242
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Language
- English
- Date published
- 06/27/2003
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094488302771
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