EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2
| Autor: | Robert M. Strongin, Na Li, Jonathan J. Abramson, Robert C. Klipp, Xander H.T. Wehrens, Martha Sibrian-Vazquez, Qiongling Wang, Tarah A. Word |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Calmodulin DNA Mutational Analysis 030204 cardiovascular system & hematology Pharmacology Inhibitory postsynaptic potential Catecholaminergic polymorphic ventricular tachycardia Ryanodine receptor 2 Article Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) Animals Medicine Myocyte Myocytes Cardiac Sheep biology business.industry Ryanodine receptor Endoplasmic reticulum Ryanodine Receptor Calcium Release Channel DNA musculoskeletal system medicine.disease Mice Mutant Strains Disease Models Animal Sarcoplasmic Reticulum 030104 developmental biology Mutation Tachycardia Ventricular cardiovascular system biology.protein Calcium Cardiology and Cardiovascular Medicine business Anti-Arrhythmia Agents |
| Zdroj: | Heart Rhythm. 15:578-586 |
| ISSN: | 1547-5271 |
| Popis: | Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disorder caused by mutations in the cardiac ryanodine receptor RyR2 that increase diastolic calcium cation (Ca2+) leak from the sarcoplasmic reticulum (SR). Calmodulin (CaM) dissociation from RyR2 has been associated with diastolic Ca2+ leak in heart failure. Objective Determine whether the tetracaine-derivative compound EL20 inhibits abnormal Ca2+ release from RyR2 in a CPVT model and investigate the underlying mechanism of inhibition. Methods Spontaneous Ca2+ sparks in cardiomyocytes and inducible ventricular tachycardia were assessed in a CPVT mouse model, which is heterozygous for the R176Q mutation in RyR2 (R176Q/+ mice) in the presence of EL20 or vehicle. Single-channel studies using sheep cardiac SR or purified RyR2 reconstituted into proteoliposomes with and without exogenous CaM were used to assess mechanisms of inhibition. Results EL20 potently inhibits abnormal Ca2+ release in R176Q/+ myocytes (half-maximal inhibitory concentration=35.4 nM) and diminishes arrhythmia in R176Q/+ mice. EL20 inhibition of single-channel activity of purified RyR2 occurs in a similar range as seen in R176Q/+ myocytes (half-maximal inhibitory concentration=8.2 nM). Inhibition of single-channel activity for cardiac SR or purified RyR2 supplemented with 100-nM or 1-μM CaM shows a 200- to 1000-fold reduction in potency. Conclusion This work provides a potential therapeutic mechanism for the development of antiarrhythmic compounds that inhibit leaky RyR2 resulting from CaM dissociation, which is often associated with failing hearts. Our data also suggest that CaM dissociation may contribute to the pathogenesis of arrhythmias with the CPVT-linked R176Q mutation. |
| Databáze: | OpenAIRE |
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