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Donald M Bers

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https://www.readbyqxmd.com/read/27902841/dynamical-effects-of-calcium-sensitive-potassium-currents-on-voltage-and-calcium-alternans
#1
Matthew Kennedy, Donald M Bers, Nipavan Chiamvimonvat, Daisuke Sato
Cardiac alternans is a precursor to life-threatening arrhythmias. Alternans can be caused by instability of the membrane voltage (Vm ), instability of the intracellular Ca (Cai ) cycling, or both. Vm dynamics and Cai dynamics are coupled via Ca-sensitive currents. In cardiac myocytes, there are several Ca-sensitive potassium (K) currents such as the slowly activating delayed rectifier current (IKs ) and the small conductance Ca-activated potassium (SK) current (ISK ). However, the role of these currents in the development of arrhythmias is not well understood...
November 30, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27861921/potassium-channels-in-the-heart-structure-function-and-regulation
#2
Eleonora Grandi, Michael C Sanguinetti, Daniel C Bartos, Donald M Bers, Ye Chen-Izu, Nipavan Chiamvimonvat, Henry M Colecraft, Brian P Delisle, Jordi Heijman, Manuel F Navedo, Sergei Noskov, Catherine Proenza, Jamie I Vandenberg, Vladimir Yarov-Yarovoy
This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K(+) Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K(+) channels...
November 13, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27810048/patient-specific-and-genome-edited-induced-pluripotent-stem-cell-derived-cardiomyocytes-elucidate-single-cell-phenotype-of-brugada-syndrome
#3
Ping Liang, Karim Sallam, Haodi Wu, Yingxin Li, Ilanit Itzhaki, Priyanka Garg, Ying Zhang, Vittavat Vermglinchan, Feng Lan, Mingxia Gu, Tingyu Gong, Yan Zhuge, Chunjiang He, Antje D Ebert, Veronica Sanchez-Freire, Jared Churko, Shijun Hu, Arun Sharma, Chi Keung Lam, Melvin M Scheinman, Donald M Bers, Joseph C Wu
BACKGROUND: Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder. OBJECTIVES: The objective of this study was to examine single cell mechanism of Brugada syndrome using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)...
November 8, 2016: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/27808412/potassium-currents-in-the-heart-functional-roles-in-repolarization-arrhythmia-and-therapeutics
#4
Nipavan Chiamvimonvat, Ye Chen-Izu, Colleen E Clancy, Isabelle Deschenes, Dobromir Dobrev, Jordi Heijman, Leighton Izu, Zhilin Qu, Crystal M Ripplinger, Jamie I Vandenberg, James N Weiss, Gideon Koren, Tamas Banyasz, Eleonora Grandi, Michael C Sanguinetti, Donald M Bers, Jeanne M Nerbonne
This is the second of the two white papers from the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium (March 3-4, 2016), a biannual event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was "K(+) Channels and Regulation", and the objectives of the conference were several fold: 1) to identify current knowledge gaps; 2) to understand what may go wrong in the diseased heart and why; 3) to identify possible novel therapeutic targets; and 4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias...
November 3, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27788149/transcriptional-profiling-of-egg-allergy-and-relationship-to-disease-phenotype
#5
Roman Kosoy, Charuta Agashe, Alexander Grishin, Donald Y Leung, Robert A Wood, Scott H Sicherer, Stacie M Jones, A Wesley Burks, Wendy F Davidson, Robert W Lindblad, Peter Dawson, Miriam Merad, Brian A Kidd, Joel T Dudley, Hugh A Sampson, M Cecilia Berin
BACKGROUND: Egg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE. OBJECTIVE: To use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from egg-allergic children who were defined as reactive (BER) or tolerant (BET) to baked egg, and from food allergic controls (AC) who were egg non-allergic...
2016: PloS One
https://www.readbyqxmd.com/read/27760856/high-throughput-screens-to-discover-small-molecule-modulators-of-ryanodine-receptor-calcium-release-channels
#6
Robyn T Rebbeck, Maram M Essawy, Florentin R Nitu, Benjamin D Grant, Gregory D Gillispie, David D Thomas, Donald M Bers, Razvan L Cornea
Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca(2+) channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca(2+) regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca(2+)], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders...
October 19, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27725286/stabilizing-ryanodine-receptor-gating-quiets-arrhythmogenic-events-in-human-heart-failure-and-atrial-fibrillation
#7
Donald M Bers
No abstract text is available yet for this article.
October 7, 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/27718550/l30a-mutation-of-phospholemman-mimics-effects-of-cardiac-glycosides-in-isolated-cardiomyocytes
#8
Ryan D Himes, Nikolai Smolin, Andreas Kukol, Julie Bossuyt, Donald M Bers, Seth L Robia
To determine if mutations made to PLM could increase PLM-NKA binding we performed scanning mutagenesis of the transmembrane domain of PLM and measured FRET between each mutant and NKA. We observed increased binding to NKA for several PLM mutants compared to WT, including L27A, L30A, and I32A. In isolated cardiomyocytes, overexpression of WT PLM increased the amplitude of the Ca2+ transient compared to GFP control. Ca2+ transient amplitude was further increased by L30A PLM overexpression. L30A mutation also delayed Ca2+ extrusion and increased the duration of cardiomyocyte contraction...
October 10, 2016: Biochemistry
https://www.readbyqxmd.com/read/27332125/stretch-activated-current-can-promote-or-suppress-cardiac-alternans-depending-on-voltage-calcium-interaction
#9
Samuel Galice, Donald M Bers, Daisuke Sato
Cardiac alternans has been linked to the onset of ventricular fibrillation and ventricular tachycardia, leading to life-threatening arrhythmias. Here, we investigated the effects of stretch-activated currents (ISAC) on alternans using a physiologically detailed model of the ventricular myocyte. We found that increasing ISAC suppresses alternans if the voltage-Ca coupling is positive or the alternans is voltage driven. However, for electromechanically discordant alternans, which occurs when the alternans is Ca driven with negative voltage-Ca coupling, increasing ISAC promotes Ca alternans...
June 21, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27318036/camkii-dependent-phosphorylation-of-ryr2-promotes-targetable-pathological-ryr2-conformational-shift
#10
Hitoshi Uchinoumi, Yi Yang, Tetsuro Oda, Na Li, Katherina M Alsina, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H T Wehrens, Donald M Bers
Diastolic calcium (Ca) leak via cardiac ryanodine receptors (RyR2) can cause arrhythmias and heart failure (HF). Ca/calmodulin (CaM)-dependent kinase II (CaMKII) is upregulated and more active in HF, promoting RyR2-mediated Ca leak by RyR2-Ser2814 phosphorylation. Here, we tested a mechanistic hypothesis that RyR2 phosphorylation by CaMKII increases Ca leak by promoting a pathological RyR2 conformation with reduced CaM affinity. Acute CaMKII activation in wild-type RyR2, and phosphomimetic RyR2-S2814D (vs. non-phosphorylatable RyR2-S2814A) knock-in mouse myocytes increased SR Ca leak, reduced CaM-RyR2 affinity, and caused a pathological shift in RyR2 conformation (detected via increased access of the RyR2 structural peptide DPc10)...
September 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27226555/s100a1-protein-does-not-compete-with-calmodulin-for-ryanodine-receptor-binding-but-structurally-alters-the-ryanodine-receptor%C3%A2-calmodulin-complex
#11
Robyn T Rebbeck, Florentin R Nitu, David Rohde, Patrick Most, Donald M Bers, David D Thomas, Razvan L Cornea
S100A1 has been suggested as a therapeutic agent to enhance myocyte Ca(2+) cycling in heart failure, but its molecular mode of action is poorly understood. Using FRET, we tested the hypothesis that S100A1 directly competes with calmodulin (CaM) for binding to intact, functional ryanodine receptors type I (RyR1) and II (RyR2) from skeletal and cardiac muscle, respectively. Our FRET readout provides an index of acceptor-labeled CaM binding near donor-labeled FKBP (FK506-binding protein 12.6) on the cytoplasmic domain of RyR in isolated sarcoplasmic reticulum vesicles...
July 22, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26789761/sarcoplasmic-reticulum-structure-and-functional-properties-that-promote-long-lasting-calcium-sparks
#12
Daisuke Sato, Thomas R Shannon, Donald M Bers
Calcium (Ca) sparks are the fundamental sarcoplasmic reticulum (SR) Ca release events in cardiac myocytes, and they have a typical duration of 20-40 ms. However, when a fraction of ryanodine receptors (RyRs) are blocked by tetracaine or ruthenium red, Ca sparks lasting hundreds of milliseconds have been observed experimentally. The fundamental mechanism underlying these extremely prolonged Ca sparks is not understood. In this study, we use a physiologically detailed mathematical model of subcellular Ca cycling to examine how Ca spark duration is influenced by the number of functional RyRs in a junctional cluster (which is reduced by tetracaine or ruthenium red) and other SR Ca handling properties...
January 19, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/26712344/individual-cardiac-mitochondria-undergo-rare-transient-permeability-transition-pore-openings
#13
Xiyuan Lu, Jennifer Q Kwong, Jeffery D Molkentin, Donald M Bers
RATIONALE: Mitochondria produce ATP, especially critical for survival of highly aerobic cells, such as cardiac myocytes. Conversely, opening of mitochondrial high-conductance and long-lasting permeability transition pores (mPTP) causes respiratory uncoupling, mitochondrial injury, and cell death. However, low conductance and transient mPTP openings (tPTP) might limit mitochondrial Ca(2+) load and be cardioprotective, but direct evidence for tPTP in cells is limited. OBJECTIVE: To directly characterize tPTP occurrence during sarcoplasmic reticulum Ca(2+) release in adult cardiac myocytes...
March 4, 2016: Circulation Research
https://www.readbyqxmd.com/read/26650851/reduced-arrhythmia-inducibility-with-calcium-calmodulin-dependent-protein-kinase-ii-inhibition-in-heart-failure-rabbits
#14
Gregory S Hoeker, Mohamed A Hanafy, Robert A Oster, Donald M Bers, Steven M Pogwizd
RATIONALE: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by β-adrenergic receptor-mediated sarcoplasmic reticulum calcium leak. OBJECTIVE: To evaluate the effect of CaMKII inhibition on ventricular tachycardia (VT) induction in conscious HF and naive rabbits. METHODS AND RESULTS: Nonischemic HF was induced by aortic insufficiency and constriction. Electrocardiograms were recorded in rabbits pretreated with vehicle (saline) or the CaMKII inhibitor KN-93 (300 μg/kg); VT was induced by infusion of increasing doses of norepinephrine (1...
March 2016: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/26450885/adrenergic-fight-or-flight-s-no-falls-on-pka-targets
#15
EDITORIAL
Donald M Bers
No abstract text is available yet for this article.
October 9, 2015: Circulation Research
https://www.readbyqxmd.com/read/26407967/slow-na-i-changes-and-positive-feedback-between-membrane-potential-and-ca-i-underlie-intermittent-early-afterdepolarizations-and-arrhythmias
#16
Yuanfang Xie, Zhandi Liao, Eleonora Grandi, Yohannes Shiferaw, Donald M Bers
BACKGROUND: Most cardiac arrhythmias occur intermittently. As a cellular precursor of lethal cardiac arrhythmias, early afterdepolarizations (EADs) during action potentials(APs) have been extensively investigated, and mechanisms for the occurrence of EADs on a beat-to-beat basis have been proposed. However, no previous study explains slow fluctuations in EADs, which may underlie intermittency of EAD trains and consequent arrhythmias. We hypothesize that the feedback of intracellular calcium and sodium concentrations ([Na](i) and [Ca](i)) that influence membrane voltage (V) can explain EAD intermittency...
December 2015: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/26324717/nuclear-calcium-calmodulin-dependent-protein-kinase-ii-signaling-enhances-cardiac-progenitor-cell-survival-and-cardiac-lineage-commitment
#17
Pearl Quijada, Nirmala Hariharan, Jonathan D Cubillo, Kristin M Bala, Jacqueline M Emathinger, Bingyan J Wang, Lucia Ormachea, Donald M Bers, Mark A Sussman, Coralie Poizat
Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) signaling in the heart regulates cardiomyocyte contractility and growth in response to elevated intracellular Ca(2+). The δB isoform of CaMKII is the predominant nuclear splice variant in the adult heart and regulates cardiomyocyte hypertrophic gene expression by signaling to the histone deacetylase HDAC4. However, the role of CaMKIIδ in cardiac progenitor cells (CPCs) has not been previously explored. During post-natal growth endogenous CPCs display primarily cytosolic CaMKIIδ, which localizes to the nuclear compartment of CPCs after myocardial infarction injury...
October 16, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26316536/s-nitrosylation-induces-both-autonomous-activation-and-inhibition-of-calcium-calmodulin-dependent-protein-kinase-ii-%C3%AE
#18
Jeffrey R Erickson, C Blake Nichols, Hitoshi Uchinoumi, Matthew L Stein, Julie Bossuyt, Donald M Bers
NO is known to modulate calcium handling and cellular signaling in the myocardium, but key targets for NO in the heart remain unidentified. Recent reports have implied that NO can activate calcium/calmodulin (Ca(2+)/CaM)-dependent protein kinase II (CaMKII) in neurons and the heart. Here we use our novel sensor of CaMKII activation, Camui, to monitor changes in the conformation and activation of cardiac CaMKII (CaMKIIδ) activity after treatment with the NO donor S-nitrosoglutathione (GSNO). We demonstrate that exposure to NO after Ca(2+)/CaM binding to CaMKIIδ results in autonomous kinase activation, which is abolished by mutation of the Cys-290 site...
October 16, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26241847/atrial-selective-targeting-of-arrhythmogenic-phase-3-early-afterdepolarizations-in-human-myocytes
#19
Stefano Morotti, Andrew D McCulloch, Donald M Bers, Andrew G Edwards, Eleonora Grandi
BACKGROUND: We have previously shown that non-equilibrium Na(+) current (INa) reactivation drives isoproterenol-induced phase-3 early afterdepolarizations (EADs) in mouse ventricular myocytes. In these cells, EAD initiation occurs secondary to potentiated sarcoplasmic reticulum Ca(2+) release and enhanced Na(+)/Ca(2+) exchange (NCX). This can be abolished by tetrodotoxin-blockade of INa, but not ranolazine, which selectively inhibits ventricular late INa. AIM: Since repolarization of human atrial myocytes is similar to mouse ventricular myocytes in that it is relatively rapid and potently modulated by Ca(2+), we investigated whether similar mechanisms can evoke EADs in human atrium...
July 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/26119742/the-mitochondrial-calcium-uniporter-selectively-matches-metabolic-output-to-acute-contractile-stress-in-the-heart
#20
Jennifer Q Kwong, Xiyuan Lu, Robert N Correll, Jennifer A Schwanekamp, Ronald J Vagnozzi, Michelle A Sargent, Allen J York, Jianyi Zhang, Donald M Bers, Jeffery D Molkentin
In the heart, augmented Ca(2+) fluxing drives contractility and ATP generation through mitochondrial Ca(2+) loading. Pathologic mitochondrial Ca(2+) overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca(2+) uptake is primarily mediated by the mitochondrial Ca(2+) uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca(2+) uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca(2+) challenge...
July 7, 2015: Cell Reports
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