ORCID Profile
0000-0002-2237-9483
Current Organisation
University of California Davis
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-03-2014
DOI: 10.1161/CIRCRESAHA.114.303391
Abstract: Calmodulin (CaM) mutations are associated with an autosomal dominant syndrome of ventricular arrhythmia and sudden death that can present with ergent clinical features of catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS). CaM binds to and inhibits ryanodine receptor (RyR2) Ca release channels in the heart, but whether arrhythmogenic CaM mutants alter RyR2 function is not known. To gain mechanistic insight into how human CaM mutations affect RyR2 Ca channels. We studied recombinant CaM mutants associated with CPVT (N54I and N98S) or LQTS (D96V, D130G, and F142L). As a group, all LQTS-associated CaM mutants (LQTS-CaMs) exhibited reduced Ca affinity, whereas CPVT-associated CaM mutants (CPVT-CaMs) had either normal or modestly lower Ca affinity. In permeabilized ventricular myocytes, CPVT-CaMs at a physiological intracellular concentration (100 nmol/L) promoted significantly higher spontaneous Ca wave and spark activity, a typical cellular phenotype of CPVT. Compared with wild-type CaM, CPVT-CaMs caused greater RyR2 single-channel open probability and showed enhanced binding affinity to RyR2. Even a 1:8 mixture of CPVT-CaM:wild-type-CaM activated Ca waves, demonstrating functional dominance. In contrast, LQTS-CaMs did not promote Ca waves and exhibited either normal regulation of RyR2 single channels (D96V) or lower RyR2-binding affinity (D130G and F142L). None of the CaM mutants altered Ca/CaM binding to CaM-kinase II. A small proportion of CPVT-CaM is sufficient to evoke arrhythmogenic Ca disturbances, whereas LQTS-CaMs do not. Our findings explain the clinical presentation and autosomal dominant inheritance of CPVT-CaM mutations and suggest that RyR2 interactions are unlikely to explain arrhythmogenicity of LQTS-CaM mutations.
Publisher: Wiley
Date: 12-02-2014
Publisher: Wiley
Date: 13-03-2015
Publisher: Springer Science and Business Media LLC
Date: 04-02-2020
DOI: 10.1038/S41598-020-58461-1
Abstract: Elevated cytoplasmic [Ca 2+ ] is characteristic in severe skeletal and cardiac myopathies, diabetes, and neurodegeneration, and partly results from increased Ca 2+ leak from sarcoplasmic reticulum stores via dysregulated ryanodine receptor (RyR) channels. Consequently, RyR is recognized as a high-value target for drug discovery to treat such pathologies. Using a FRET-based high-throughput screening assay that we previously reported, we identified small-molecule compounds that modulate the skeletal muscle channel isoform (RyR1) interaction with calmodulin and FK506 binding protein 12.6. Two such compounds, chloroxine and myricetin, increase FRET and inhibit [ 3 H]ryanodine binding to RyR1 at nanomolar Ca 2+ . Both compounds also decrease RyR1 Ca 2+ leak in human skinned skeletal muscle fibers. Furthermore, we identified compound concentrations that reduced leak by 50% but only slightly affected Ca 2+ release in excitation-contraction coupling, which is essential for normal muscle contraction. This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/CIRCEP.113.001666
Abstract: Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca 2+ current (I CaL ) reactivation or sarcoplasmic reticulum Ca 2+ release and Na + /Ca 2+ exchange. In large mammals the positive action potential plateau promotes I CaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between I CaL and the repolarizing K + currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit I CaL reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations. In Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca 2+ release, and initiated EADs below the I CaL activation range (–47±0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not ranolazine), suggesting that sarcoplasmic reticulum Ca 2+ release and Na + current (I Na ), but not late I Na , are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca 2+ release and Na + /Ca 2+ exchange shape late action potential repolarization to favor nonequilibrium reactivation of I Na and thereby drive the EAD upstroke. Action potential cl experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40–60 μmol/L) for which lidocaine remains specific for inactivated Na + channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium I Na dynamics underlie murine EADs. Nonequilibrium reactivation of I Na drives murine EADs.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-11-2021
Abstract: Found in translation: We present quantitative tools that map cardiac myocyte physiology and pharmacology across species.
Publisher: Elsevier BV
Date: 2022
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Donald Bers.