ArticleThe Biochemical journal2007
K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association.
Article in The Biochemical journal, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 89 citations in OpenAlex.
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- Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.Current heart failure reports · 2025Review
- Treating Cardiovascular Disorders with Personalized Medicine.Cardiovascular & hematological disorders drug targets · 2025Review
- Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level.Journal of molecular and cellular cardiology · 2024Article
- Clustering properties of the cardiac ryanodine receptor in health and heart failure.Journal of molecular and cellular cardiology · 2023Review
- ASIC1a is required for neuronal activation via low-intensity ultrasound stimulation in mouse brain.eLife · 2021Article
- Butyrate Feeding Reverses CypD-Related Mitoflash Phenotypes in Mouse Myofibers.International journal of molecular sciences · 2021Article
- Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors.British journal of pharmacology · 2020Article
- Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.Expert opinion on therapeutic targets · 2020Review
- Calcium Homeostasis in Ventricular Myocytes of Diabetic Cardiomyopathy.Journal of diabetes research · 2020Review
- Two pools of IRE1α in cardiac and skeletal muscle cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Control of cardiac ryanodine receptor by sarcoplasmic reticulum luminal CaThe Journal of general physiology · 2017Review
- Total internal reflectance fluorescence imaging of genetically engineered ryanodine receptor-targeted CaCell calcium · 2017Article
- Calcium Signaling and Cardiac Arrhythmias.Circulation research · 2017Review
- Heart failure modulates electropharmacological characteristics of sinoatrial nodes.Experimental and therapeutic medicine · 2017Article
- Murine Electrophysiological Models of Cardiac Arrhythmogenesis.Physiological reviews · 2017Review
- Distribution and Function of Cardiac Ryanodine Receptor Clusters in Live Ventricular Myocytes.The Journal of biological chemistry · 2015Article
- Targeting cardiomyocyte Ca2+ homeostasis in heart failure.Current pharmaceutical design · 2015Review
- Personalized medicine to treat arrhythmias.Current opinion in pharmacology · 2014Review
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8 authors at 1 institution in 1 country.
Funding
Abstract
K201 (JTV519), a benzothiazepine derivative, has been shown to possess anti-arrhythmic and cardioprotective properties, but the mechanism of its action is both complex and controversial. It is believed to stabilize the closed state of the RyR2 (cardiac ryanodine receptor) by increasing its affinity for the FKBP12.6 (12.6 kDa FK506 binding protein) [Wehrens, Lehnart, Reiken, Deng, Vest, Cervantes, Coromilas, Landry and Marks (2004) Science 304, 292-296]. In the present study, we investigated the effect of K201 on spontaneous Ca2+ release induced by Ca2+ overload in rat ventricular myocytes and in HEK-293 cells (human embryonic kidney cells) expressing RyR2 and the role of FKBP12.6 in the action of K201. We found that K201 abolished spontaneous Ca2+ release in cardiac myocytes in a concentration-dependent manner. Treating ventricular myocytes with FK506 to dissociate FKBP12.6 from RyR2 did not affect the suppression of spontaneous Ca2+ release by K201. Similarly, K201 was able to suppress spontaneous Ca2+ release in FK506-treated HEK-293 cells co-expressing RyR2 and FKBP12.6. Furthermore, K201 suppressed spontaneous Ca2+ release in HEK-293 cells expressing RyR2 alone and in cells co-expressing RyR2 and FKBP12.6 with the same potency. In addition, K201 inhibited [3H]ryanodine binding to RyR2-wt (wild-type) and an RyR2 mutant linked to ventricular tachycardia and sudden death, N4104K, in the absence of FKBP12.6. These observations demonstrate that FKBP12.6 is not involved in the inhibitory action of K201 on spontaneous Ca2+ release. Our results also suggest that suppression of spontaneous Ca2+ release and the activity of RyR2 contributes, at least in part, to the anti-arrhythmic properties of K201.
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