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Donald M Bers

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https://www.readbyqxmd.com/read/28618338/markolab-a-simulator-to-study-ionic-channel-s-stochastic-behavior
#1
Robson Rodrigues da Silva, Daniel Gustavo Goroso, Donald M Bers, José Luis Puglisi
Mathematical models of the cardiac cell have started to include markovian representations of the ionic channels instead of the traditional Hodgkin & Huxley formulations. There are many reasons for this: Markov models are not restricted to the idea of independent gates defining the channel, they allow more complex description with specific transitions between open, closed or inactivated states, and more importantly those states can be closely related to the underlying channel structure and conformational changes...
August 1, 2017: Computers in Biology and Medicine
https://www.readbyqxmd.com/read/28587810/subcellular-localization-of-na-k-atpase-isoforms-in-ventricular-myocytes
#2
Garrick K Yuen, Samuel Galice, Donald M Bers
The sodium/potassium ATPase (NKA) is essential for establishing the normal intracellular [Na(+)] and [K(+)] and transmembrane gradients that are essential for many cellular functions, including cardiac electrophysiology and contractility. Different NKA isoforms exhibit differential expression levels, cellular localization, and function in different tissues and species. Prior work has indicated that the NKA-α1 isoform is quantitatively predominant in cardiac myocytes, but that the α2 isoform is preferentially concentrated in the transverse tubules (TT), possibly at junctions with the sarcoplasmic reticulum (SR) where α2 may preferentially modulate cardiac contractility...
July 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28476660/%C3%AE-adrenergic-induced-sr-ca-2-leak-is-mediated-by-an-epac-nos-pathway
#3
Laëtitia Pereira, Dan J Bare, Samuel Galice, Thomas R Shannon, Donald M Bers
Cardiac β-adrenergic receptors (β-AR) and Ca(2+)-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca(2+) signaling. Elevated diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca(2+) leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1)...
July 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28425435/fret-biosensor-uncovers-camp-nano-domains-at-%C3%AE-adrenergic-targets-that-dictate-precise-tuning-of-cardiac-contractility
#4
Nicoletta C Surdo, Marco Berrera, Andreas Koschinski, Marcella Brescia, Matias R Machado, Carolyn Carr, Peter Wright, Julia Gorelik, Stefano Morotti, Eleonora Grandi, Donald M Bers, Sergio Pantano, Manuela Zaccolo
Compartmentalized cAMP/PKA signalling is now recognized as important for physiology and pathophysiology, yet a detailed understanding of the properties, regulation and function of local cAMP/PKA signals is lacking. Here we present a fluorescence resonance energy transfer (FRET)-based sensor, CUTie, which detects compartmentalized cAMP with unprecedented accuracy. CUTie, targeted to specific multiprotein complexes at discrete plasmalemmal, sarcoplasmic reticular and myofilament sites, reveals differential kinetics and amplitudes of localized cAMP signals...
April 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28370016/k-channels-and-cardiac-electrophysiology
#5
EDITORIAL
Donald M Bers, Ye Chen-Izu
No abstract text is available yet for this article.
April 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28111350/antiarrhythmic-effects-of-interleukin-1-inhibition-after-myocardial-infarction
#6
Nicole M De Jesus, Lianguo Wang, Johnny Lai, Robert R Rigor, Samantha D Francis Stuart, Donald M Bers, Merry L Lindsey, Crystal M Ripplinger
BACKGROUND: Interleukin 1β (IL-1β) is a key regulator of the inflammatory response after myocardial infarction (MI) by modulating immune cell recruitment, cytokine production, and extracellular matrix turnover. Elevated levels of IL-1β are associated with adverse remodeling, and inhibition of IL-1 signaling after MI results in improved contractile function. OBJECTIVE: The goal of this study was to determine whether IL-1 signaling also contributes to post-MI arrhythmogenesis...
May 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28057778/calming-down-arrhythmogenic-calmodulinopathies-via-a-precision-medicine-approach
#7
EDITORIAL
Donald M Bers
No abstract text is available yet for this article.
January 6, 2017: Circulation Research
https://www.readbyqxmd.com/read/28008618/quantitative-analysis-of-the-ca-2-dependent-regulation-of-delayed-rectifier-k-current-iks-in-rabbit-ventricular-myocytes
#8
Daniel C Bartos, Stefano Morotti, Kenneth S Ginsburg, Eleonora Grandi, Donald M Bers
KEY POINTS: [Ca(2+) ]i enhanced rabbit ventricular slowly activating delayed rectifier K(+) current (IKs ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K(+) current (IKr ) amplitude and voltage dependence were unaffected by high [Ca(2+) ]i . When measuring or simulating IKs during an action potential, IKs was not different during a physiological Ca(2+) transient or when [Ca(2+) ]i was buffered to 500 nm...
April 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/27902841/dynamical-effects-of-calcium-sensitive-potassium-currents-on-voltage-and-calcium-alternans
#9
Matthew Kennedy, Donald M Bers, Nipavan Chiamvimonvat, Daisuke Sato
KEY POINTS: A mathematical model of a small conductance Ca(2)(+) -activated potassium (SK) channel was developed and incorporated into a physiologically detailed ventricular myocyte model. Ca(2+) -sensitive K(+) currents promote negative intracellular Ca(2+) to membrane voltage (CAi(2+) → Vm ) coupling. Increase of Ca(2+) -sensitive K(+) currents can be responsible for electromechanically discordant alternans and quasiperiodic oscillations at the cellular level. At the tissue level, Turing-type instability can occur when Ca(2+) -sensitive K(+) currents are increased...
April 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/27861921/potassium-channels-in-the-heart-structure-function-and-regulation
#10
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...
April 1, 2017: 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
#11
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
#12
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 Cardiovascular Symposium Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias (3-4 March 2016), a biennial 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 severalfold: (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...
April 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/27788149/transcriptional-profiling-of-egg-allergy-and-relationship-to-disease-phenotype
#13
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
#14
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...
February 2017: SLAS Discovery
https://www.readbyqxmd.com/read/27725286/stabilizing-ryanodine-receptor-gating-quiets-arrhythmogenic-events-in-human-heart-failure-and-atrial-fibrillation
#15
EDITORIAL
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
#16
Ryan D Himes, Nikolai Smolin, Andreas Kukol, Julie Bossuyt, Donald M Bers, Seth L Robia
To determine if mutations introduced into phospholemman (PLM) could increase the level of PLM-Na,K-ATPase (NKA) binding, we performed scanning mutagenesis of the transmembrane domain of PLM and measured Förster resonance energy transfer (FRET) between each mutant and NKA. We observed an increased level of binding to NKA for several PLM mutants compared to that of the wild type (WT), including L27A, L30A, and I32A. In isolated cardiomyocytes, overexpression of WT PLM increased the amplitude of the Ca(2+) transient compared to the GFP control...
November 8, 2016: Biochemistry
https://www.readbyqxmd.com/read/27332125/stretch-activated-current-can-promote-or-suppress-cardiac-alternans-depending-on-voltage-calcium-interaction
#17
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
#18
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
#19
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
#20
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
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