Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 304 (5668): 292-296

Copyright © 2004 by the American Association for the Advancement of Science

Protection from Cardiac Arrhythmia Through Ryanodine Receptor-Stabilizing Protein Calstabin2

Xander H. T. Wehrens,1,2* Stephan E. Lehnart,1,2* Steven R. Reiken,1,2 Shi-Xian Deng,3 John A. Vest,1,2,3 Daniel Cervantes,3 James Coromilas,3 Donald W. Landry,3 Andrew R. Marks1,2,3{dagger}

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.

1 Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
2 Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
3 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

Back to Top

* These authors contributed equally to this paper.

{dagger} To whom correspondence should be addressed. E-mail: arm42{at}

Role of RyR2 Phosphorylation in Heart Failure and Arrhythmias: Controversies Around Ryanodine Receptor Phosphorylation in Cardiac Disease.
D. Dobrev and X. H. T. Wehrens (2014)
Circ. Res. 114, 1311-1319
   Abstract »    Full Text »    PDF »
Mechanisms of Altered Ca2+ Handling in Heart Failure.
M. Luo and M. E. Anderson (2013)
Circ. Res. 113, 690-708
   Abstract »    Full Text »    PDF »
Bradycardia alters Ca2+ dynamics enhancing dispersion of repolarization and arrhythmia risk.
J. J. Kim, J. Nemec, R. Papp, R. Strongin, J. J. Abramson, and G. Salama (2013)
Am J Physiol Heart Circ Physiol 304, H848-H860
   Abstract »    Full Text »    PDF »
Protective Effect of K201 on Isoproterenol-Induced and Ischemic-Reperfusion-Induced Ventricular Arrhythmias in the Rat: Comparison With Diltiazem.
N. Otani, R. Matsuda, K. Oda, S. Nishino, T. Inoue, and N. Kaneko (2013)
Journal of Cardiovascular Pharmacology and Therapeutics 18, 184-190
   Abstract »    Full Text »    PDF »
A network-oriented perspective on cardiac calcium signaling.
C. H. George, D. Parthimos, and N. C. Silvester (2012)
Am J Physiol Cell Physiol 303, C897-C910
   Abstract »    Full Text »    PDF »
Catecholaminergic Polymorphic Ventricular Tachycardia.
A. Leenhardt, I. Denjoy, and P. Guicheney (2012)
Circ Arrhythm Electrophysiol 5, 1044-1052
   Full Text »    PDF »
Calcium Leak Through Ryanodine Receptors Leads to Atrial Fibrillation in 3 Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia.
J. Shan, W. Xie, M. Betzenhauser, S. Reiken, B.-X. Chen, A. Wronska, and A. R. Marks (2012)
Circ. Res. 111, 708-717
   Abstract »    Full Text »    PDF »
Modulation of Cardiac Contractility by the Phopholamban/SERCA2a Regulatome.
E. G. Kranias and R. J. Hajjar (2012)
Circ. Res. 110, 1646-1660
   Abstract »    Full Text »    PDF »
Ryanodine Receptor Phosphorylation and Heart Failure: Phasing Out S2808 and "Criminalizing" S2814.
H. H. Valdivia (2012)
Circ. Res. 110, 1398-1402
   Full Text »    PDF »
Acute Coronary Events.
A. Arbab-Zadeh, M. Nakano, R. Virmani, and V. Fuster (2012)
Circulation 125, 1147-1156
   Full Text »    PDF »
Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments.
C. van der Werf, A. H. Zwinderman, and A. A. M. Wilde (2012)
Europace 14, 175-183
   Abstract »    Full Text »    PDF »
Designing Calcium Release Channel Inhibitors with Enhanced Electron Donor Properties: Stabilizing the Closed State of Ryanodine Receptor Type 1.
Y. Ye, D. Yaeger, L. J. Owen, J. O. Escobedo, J. Wang, J. D. Singer, R. M. Strongin, and J. J. Abramson (2012)
Mol. Pharmacol. 81, 53-62
   Abstract »    Full Text »    PDF »
Inherited Dysfunction of Sarcoplasmic Reticulum Ca2+ Handling and Arrhythmogenesis.
S. G. Priori and S. R. W. Chen (2011)
Circ. Res. 108, 871-883
   Abstract »    Full Text »    PDF »
The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications.
D. Dobrev, N. Voigt, and X. H. T. Wehrens (2011)
Cardiovasc Res 89, 734-743
   Abstract »    Full Text »    PDF »
Acute atrial arrhythmogenicity and altered Ca2+ homeostasis in murine RyR2-P2328S hearts.
Y. Zhang, J. A. Fraser, K. Jeevaratnam, X. Hao, S. S. Hothi, A. A. Grace, M. Lei, and C. L.- H. Huang (2011)
Cardiovasc Res 89, 794-804
   Abstract »    Full Text »    PDF »
Ryanodine Receptor Phosphorylation by Calcium/Calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice With Heart Failure.
R. J. van Oort, M. D. McCauley, S. S. Dixit, L. Pereira, Y. Yang, J. L. Respress, Q. Wang, A. C. De Almeida, D. G. Skapura, M. E. Anderson, et al. (2010)
Circulation 122, 2669-2679
   Abstract »    Full Text »    PDF »
Perspectives on: Local calcium signaling: Subcellular Ca2+ signaling in the heart: the role of ryanodine receptor sensitivity.
B. L. Prosser, C. W. Ward, and W. J. Lederer (2010)
J. Gen. Physiol. 136, 135-142
   Full Text »    PDF »
Ca2+ Cycling and New Therapeutic Approaches for Heart Failure.
A.-M. Lompre, R. J. Hajjar, S. E. Harding, E. G. Kranias, M. J. Lohse, and A. R. Marks (2010)
Circulation 121, 822-830
   Full Text »    PDF »
Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.
J. Fauconnier, J. Thireau, S. Reiken, C. Cassan, S. Richard, S. Matecki, A. R. Marks, and A. Lacampagne (2010)
PNAS 107, 1559-1564
   Abstract »    Full Text »    PDF »
Sudden Infant Death Syndrome in Mice With an Inherited Mutation in RyR2.
N. Mathur, S. Sood, S. Wang, R. J. van Oort, S. Sarma, N. Li, D. G. Skapura, J. H. Bayle, M. Valderrabano, and X. H.T. Wehrens (2009)
Circ Arrhythm Electrophysiol 2, 677-685
   Abstract »    Full Text »    PDF »
Role of coupled gating between cardiac ryanodine receptors in the genesis of triggered arrhythmias.
W. Chen, J. A. Wasserstrom, and Y. Shiferaw (2009)
Am J Physiol Heart Circ Physiol 297, H171-H180
   Abstract »    Full Text »    PDF »
Mineralocorticoid Modulation of Cardiac Ryanodine Receptor Activity Is Associated With Downregulation of FK506-Binding Proteins.
A. M. Gomez, A. Rueda, Y. Sainte-Marie, L. Pereira, S. Zissimopoulos, X. Zhu, R. Schaub, E. Perrier, R. Perrier, C. Latouche, et al. (2009)
Circulation 119, 2179-2187
   Abstract »    Full Text »    PDF »
Targeting calcium handling in arrhythmias.
G. Antoons and K. R. Sipido (2008)
Europace 10, 1364-1369
   Abstract »    Full Text »    PDF »
Conditional FKBP12.6 Overexpression in Mouse Cardiac Myocytes Prevents Triggered Ventricular Tachycardia Through Specific Alterations in Excitation- Contraction Coupling.
B. Gellen, M. Fernandez-Velasco, F. Briec, L. Vinet, K. LeQuang, P. Rouet-Benzineb, J.-P. Benitah, M. Pezet, G. Palais, N. Pellegrin, et al. (2008)
Circulation 117, 1778-1786
   Abstract »    Full Text »    PDF »
Remodeling of ryanodine receptor complex causes "leaky" channels: A molecular mechanism for decreased exercise capacity.
A. M. Bellinger, S. Reiken, M. Dura, P. W. Murphy, S.-X. Deng, D. W. Landry, D. Nieman, S. E. Lehnart, M. Samaru, A. LaCampagne, et al. (2008)
PNAS 105, 2198-2202
   Abstract »    Full Text »    PDF »
Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts.
T. Yamamoto, M. Yano, X. Xu, H. Uchinoumi, H. Tateishi, M. Mochizuki, T. Oda, S. Kobayashi, N. Ikemoto, and M. Matsuzaki (2008)
Circulation 117, 762-772
   Abstract »    Full Text »    PDF »
Toward Biologically Targeted Therapy of Calcium Cycling Defects in Heart Failure.
Y. Ikeda, M. Hoshijima, and K. R. Chien (2008)
Physiology 23, 6-16
   Abstract »    Full Text »    PDF »
Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance?.
C. H. George (2008)
Cardiovasc Res 77, 302-314
   Abstract »    Full Text »    PDF »
Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin.
N. Liu and S. G. Priori (2008)
Cardiovasc Res 77, 293-301
   Abstract »    Full Text »    PDF »
Removal of FKBP12.6 Does Not Alter the Conductance and Activation of the Cardiac Ryanodine Receptor or the Susceptibility to Stress-induced Ventricular Arrhythmias.
J. Xiao, X. Tian, P. P. Jones, J. Bolstad, H. Kong, R. Wang, L. Zhang, H. J. Duff, A. M. Gillis, S. Fleischer, et al. (2007)
J. Biol. Chem. 282, 34828-34838
   Abstract »    Full Text »    PDF »
Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function.
S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al. (2007)
Circulation 116, 2325-2345
   Abstract »    Full Text »    PDF »
RyR1-specific requirement for depolarization-induced Ca2+ sparks in urinary bladder smooth muscle.
N. Fritz, J.-L. Morel, L. H. Jeyakumar, S. Fleischer, P. D. Allen, J. Mironneau, and N. Macrez (2007)
J. Cell Sci. 120, 3784-3791
   Abstract »    Full Text »    PDF »
Inhibition of SR Ca2+ uptake: A novel action of the RyR2-FKBP12.6 antagonist K201.
A. F. James (2007)
Cardiovasc Res 76, 199-201
   Full Text »    PDF »
Expanding Spectrum of Human RYR2-Related Disease: New Electrocardiographic, Structural, and Genetic Features.
Z. A. Bhuiyan, M. P. van den Berg, J. P. van Tintelen, M. T.E. Bink-Boelkens, A. C.P. Wiesfeld, M. Alders, A. V. Postma, I. van Langen, M. M.A.M. Mannens, and A. A.M. Wilde (2007)
Circulation 116, 1569-1576
   Abstract »    Full Text »    PDF »
Mechanisms of Human Arrhythmia Syndromes: Abnormal Cardiac Macromolecular Interactions.
P. J. Mohler and X. H. T. Wehrens (2007)
Physiology 22, 342-350
   Abstract »    Full Text »    PDF »
Removal of Fkbp12/12.6 From Endothelial Ryanodine Receptors Leads to an Intracellular Calcium Leak and Endothelial Dysfunction.
C. Long, L. G. Cook, G.-Y. Wu, and B. M. Mitchell (2007)
Arterioscler Thromb Vasc Biol 27, 1580-1586
   Abstract »    Full Text »    PDF »
Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein.
S. Zissimopoulos, N. Docrat, and F. A. Lai (2007)
J. Biol. Chem. 282, 6976-6983
   Abstract »    Full Text »    PDF »
CaM or cAMP: Linking {beta}-Adrenergic Stimulation to 'Leaky' RyRs.
K. R. Sipido (2007)
Circ. Res. 100, 296-298
   Full Text »    PDF »
Altered Cardiac Myocyte Ca Regulation In Heart Failure..
D. M. Bers (2006)
Physiology 21, 380-387
   Abstract »    Full Text »    PDF »
Phosphorylation of the Cardiac Ryanodine Receptor by Ca2+/Calmodulin-Dependent Protein Kinase II: The Dominating Twin of Protein Kinase A?.
J. Kockskamper and B. Pieske (2006)
Circ. Res. 99, 333-335
   Full Text »    PDF »
Life, Sudden Death, and Intracellular Calcium.
D.A. Eisner, L.A. Venetucci, and A.W. Trafford (2006)
Circ. Res. 99, 223-224
   Full Text »    PDF »
Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia: Insights From a RyR2 R4496C Knock-In Mouse Model.
N. Liu, B. Colombi, M. Memmi, S. Zissimopoulos, N. Rizzi, S. Negri, M. Imbriani, C. Napolitano, F. A. Lai, and S. G. Priori (2006)
Circ. Res. 99, 292-298
   Abstract »    Full Text »    PDF »
Profile of Andrew R. Marks.
P. Downey (2006)
PNAS 103, 8915-8917
   Full Text »    PDF »
Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy.
M. Yamada, Y. Ikeda, M. Yano, K. Yoshimura, S. Nishino, H. Aoyama, L. Wang, H. Aoki, and M. Matsuzaki (2006)
FASEB J 20, 1197-1199
   Abstract »    Full Text »    PDF »
Is the Ryanodine Receptor a Target for Antiarrhythmic Therapy?.
C. Pott and J. I. Goldhaber (2006)
Circ. Res. 98, 1232-1233
   Full Text »    PDF »
Reducing Ryanodine Receptor Open Probability as a Means to Abolish Spontaneous Ca2+ Release and Increase Ca2+ Transient Amplitude in Adult Ventricular Myocytes.
L.A. Venetucci, A.W. Trafford, M.E. Diaz, S.C. O'Neill, and D.A. Eisner (2006)
Circ. Res. 98, 1299-1305
   Abstract »    Full Text »    PDF »
Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.
S. E. Lehnart, C. Terrenoire, S. Reiken, X. H. T. Wehrens, L.-S. Song, E. J. Tillman, S. Mancarella, J. Coromilas, W. J. Lederer, R. S. Kass, et al. (2006)
PNAS 103, 7906-7910
   Abstract »    Full Text »    PDF »
Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: Rescue of heart failure by calstabin2 in mice.
F. Huang, J. Shan, S. Reiken, X. H. T. Wehrens, and A. R. Marks (2006)
PNAS 103, 3456-3461
   Abstract »    Full Text »    PDF »
Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression.
X. H. T. Wehrens, S. E. Lehnart, S. Reiken, J. A. Vest, A. Wronska, and A. R. Marks (2006)
PNAS 103, 511-518
   Abstract »    Full Text »    PDF »
New Cardioprotective Agent K201 Is Natriuretic and Glomerular Filtration Rate Enhancing.
O. Lisy and J. C. Burnett Jr (2006)
Circulation 113, 246-251
   Abstract »    Full Text »    PDF »
The Fire From Within: The Biggest Ca2+ Channel Erupts and Dribbles.
M. E. Anderson (2005)
Circ. Res. 97, 1213-1215
   Full Text »    PDF »
Nuclear Targeting of Akt Enhances Ventricular Function and Myocyte Contractility.
M. Rota, A. Boni, K. Urbanek, M. E. Padin-Iruegas, T. J. Kajstura, G. Fiore, H. Kubo, E. H. Sonnenblick, E. Musso, S. R. Houser, et al. (2005)
Circ. Res. 97, 1332-1341
   Abstract »    Full Text »    PDF »
Correction of Defective Interdomain Interaction Within Ryanodine Receptor by Antioxidant Is a New Therapeutic Strategy Against Heart Failure.
M. Yano, S. Okuda, T. Oda, T. Tokuhisa, H. Tateishi, M. Mochizuki, T. Noma, M. Doi, S. Kobayashi, T. Yamamoto, et al. (2005)
Circulation 112, 3633-3643
   Abstract »    Full Text »    PDF »
Reconstitution of local Ca2+ signaling between cardiac L-type Ca2+ channels and ryanodine receptors: insights into regulation by FKBP12.6.
S. A. Goonasekera, S. R. W. Chen, and R. T. Dirksen (2005)
Am J Physiol Cell Physiol 289, C1476-C1484
   Abstract »    Full Text »    PDF »
Intracellular Calcium Handling Dysfunction and Arrhythmogenesis: A New Challenge for the Electrophysiologist.
S. G. Priori and C. Napolitano (2005)
Circ. Res. 97, 1077-1079
   Full Text »    PDF »
Ryanodine receptor binding to FKBP12 is modulated by channel activation state.
J.-L. Jones, D. F. Reynolds, F. A. Lai, and L. M. Blayney (2005)
J. Cell Sci. 118, 4613-4619
   Abstract »    Full Text »    PDF »
Modulation of CaV1.2 Channels by Mg2+ Acting at an EF-hand Motif in the COOH-terminal Domain.
S. Brunet, T. Scheuer, R. Klevit, and W. A. Catterall (2005)
J. Gen. Physiol. 126, 311-323
   Abstract »    Full Text »    PDF »
Catecholaminergic polymorphic ventricular tachycardia: Recent mechanistic insights.
K. Kontula, P. J. Laitinen, A. Lehtonen, L. Toivonen, M. Viitasalo, and H. Swan (2005)
Cardiovasc Res 67, 379-387
   Abstract »    Full Text »    PDF »
A. Pedram, M. Razandi, M. Aitkenhead, and E. R. Levin (2005)
J. Biol. Chem. 280, 26339-26348
   Abstract »    Full Text »    PDF »
Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure.
X. H. T. Wehrens, S. E. Lehnart, S. Reiken, R. van der Nagel, R. Morales, J. Sun, Z. Cheng, S.-X. Deng, L. J. de Windt, D. W. Landry, et al. (2005)
PNAS 102, 9607-9612
   Abstract »    Full Text »    PDF »
Defective Ryanodine Receptor Interdomain Interactions May Contribute to Intracellular Ca2+ Leak: A Novel Therapeutic Target in Heart Failure.
S. E. Lehnart, X. H.T. Wehrens, and A. R. Marks (2005)
Circulation 111, 3342-3346
   Full Text »    PDF »
Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure.
T. Oda, M. Yano, T. Yamamoto, T. Tokuhisa, S. Okuda, M. Doi, T. Ohkusa, Y. Ikeda, S. Kobayashi, N. Ikemoto, et al. (2005)
Circulation 111, 3400-3410
   Abstract »    Full Text »    PDF »
Intracellular Calcium Dynamics and Anisotropic Reentry in Isolated Canine Pulmonary Veins and Left Atrium.
C.-C. Chou, M. Nihei, S. Zhou, A. Tan, A. Kawase, E. S. Macias, M. C. Fishbein, S.-F. Lin, and P.-S. Chen (2005)
Circulation 111, 2889-2897
   Abstract »    Full Text »    PDF »
Can Novel Therapies for Arrhythmias Caused by Spontaneous Sarcoplasmic Reticulum Ca2+ Release be Developed Using Mouse Models?.
S. R. Houser (2005)
Circ. Res. 96, 1031-1032
   Full Text »    PDF »
Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation.
J. A. Vest, X. H.T. Wehrens, S. R. Reiken, S. E. Lehnart, D. Dobrev, P. Chandra, P. Danilo, U. Ravens, M. R. Rosen, and A. R. Marks (2005)
Circulation 111, 2025-2032
   Abstract »    Full Text »    PDF »
Mutant cardiac ryanodine receptors and ventricular arrhythmias: is 'gain-of-function' obligatory?.
A. M. Gomez and S. Richard (2004)
Cardiovasc Res 64, 3-5
   Full Text »    PDF »
Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death.
N. Lowri Thomas, C. H. George, and F. Anthony Lai (2004)
Cardiovasc Res 64, 52-60
   Abstract »    Full Text »    PDF »
Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak.
S. E. Lehnart, X. H.T. Wehrens, P. J. Laitinen, S. R. Reiken, S.-X. Deng, Z. Cheng, D. W. Landry, K. Kontula, H. Swan, and A. R. Marks (2004)
Circulation 109, 3208-3214
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882