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Ion channel, herg

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https://www.readbyqxmd.com/read/29573276/sinusoidal-voltage-protocols-for-rapid-characterisation-of-ion-channel-kinetics
#1
Kylie A Beattie, Adam P Hill, Rémi Bardenet, Yi Cui, Jamie I Vandenberg, David J Gavaghan, Teun P de Boer, Gary R Mirams
Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current...
March 24, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29563525/investigating-the-state-dependence-of-drug-binding-in-herg-channels-using-a-trapped-open-channel-phenotype
#2
Samrat Thouta, Garman Lo, Lukas Grajauskas, Tom Claydon
The hERG channel is a key player in repolarization of the cardiac action potential. Pharmacological blockade of hERG channels depletes the cardiac repolarization reserve, increasing the risk of cardiac arrhythmias. The promiscuous nature of drug interactions with hERG presents a therapeutic challenge for drug design and development. Despite considerable effort, the mechanisms of drug binding remain incompletely understood. One proposed mechanism is that high-affinity drug binding preferentially occurs when channels are in the inactivated state...
March 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29555184/proarrhythmia-risk-prediction-using-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#3
Daiju Yamazaki, Takashi Kitaguchi, Masakazu Ishimura, Tomohiko Taniguchi, Atsuhiro Yamanishi, Daisuke Saji, Etsushi Takahashi, Masao Oguchi, Yuta Moriyama, Sanae Maeda, Kaori Miyamoto, Kaoru Morimura, Hiroki Ohnaka, Hiroyuki Tashibu, Yuko Sekino, Norimasa Miyamoto, Yasunari Kanda
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to become a useful tool for proarrhythmia risk prediction in the non-clinical drug development phase. Several features including electrophysiological properties, ion channel expression profile and drug responses were investigated using commercially available hiPSC-CMs, such as iCell-CMs and Cor.4U-CMs. Although drug-induced arrhythmia has been extensively examined by microelectrode array (MEA) assays in iCell-CMs, it has not been fully understood an availability of Cor...
March 3, 2018: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29536448/machine-learning-based-modeling-of-drug-toxicity
#4
Jing Lu, Dong Lu, Zunyun Fu, Mingyue Zheng, Xiaomin Luo
Toxicity is an important reason for the failure of drug research and development (R&D). The traditional experimental testings for chemical toxicity profile are costly and time-consuming. Therefore, it is attractive to develop the effective and accurate alternatives, such as in silico prediction models. In this review, we discuss the practical use of some prediction models on three toxicity end points, including acute toxicity, carcinogenicity, and inhibition of the human ether-a-go-go-related gene ion channel (hERG)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29494279/a-multiplatform-strategy-for-the-discovery-of-conventional-monoclonal-antibodies-that-inhibit-the-voltage-gated-potassium-channel-kv1-3
#5
Janna Bednenko, Rian Harriman, Lore Mariën, Hai M Nguyen, Alka Agrawal, Ashot Papoyan, Yelena Bisharyan, Joanna Cardarelli, Donna Cassidy-Hanley, Ted Clark, Darlene Pedersen, Yasmina Abdiche, William Harriman, Bas van der Woning, Hans de Haard, Ellen Collarini, Heike Wulff, Paul Colussi
Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high-level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein...
March 1, 2018: MAbs
https://www.readbyqxmd.com/read/29474817/activation-of-the-unfolded-protein-response-downregulates-cardiac-ion-channels-in-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#6
Man Liu, Guangbin Shi, Anyu Zhou, Cassady E Rupert, Kareen L K Coulombe, Samuel C Dudley
RATIONALE: Heart failure is characterized by electrical remodeling that contributes to arrhythmic risk. The unfolded protein response (UPR) is active in heart failure and can decrease protein levels by increasing mRNA decay, accelerating protein degradation, and inhibiting protein translation. OBJECTIVE: Therefore, we investigated whether the UPR downregulated cardiac ion channels that may contribute to arrhythmogenic electrical remodeling. METHODS: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study cardiac ion channels...
February 21, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29465167/computer-simulations-reveal-a-novel-blocking-mode-of-the-herg-ion-channel-by-the-antiarrhythmic-agent-clofilium
#7
Daniel Șterbuleac, Călin Lucian Maniu
The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations...
February 21, 2018: Molecular Informatics
https://www.readbyqxmd.com/read/29456831/early-afterdepolarisation-tendency-as-a-simulated-pro-arrhythmic-risk-indicator
#8
Beth McMillan, David J Gavaghan, Gary R Mirams
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology...
November 1, 2017: Toxicology Research
https://www.readbyqxmd.com/read/29449809/digging-into-lipid-membrane-permeation-for-cardiac-ion-channel-blocker-d-sotalol-with-all-atom-simulations
#9
Kevin R DeMarco, Slava Bekker, Colleen E Clancy, Sergei Y Noskov, Igor Vorobyov
Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29348631/dynamic-all-optical-drug-screening-on-cardiac-voltage-gated-ion-channels
#10
Jonas Streit, Sonja Kleinlogel
Voltage-gated ion channels (VGCs) are prime targets for the pharmaceutical industry, but drug profiling on VGCs is challenging, since drug interactions are confined to specific conformational channel states mediated by changes in transmembrane potential. Here we combined various optogenetic tools to develop dynamic, high-throughput drug profiling assays with defined light-step protocols to interrogate VGC states on a millisecond timescale. We show that such light-induced electrophysiology (LiEp) yields high-quality pharmacological data with exceptional screening windows for drugs acting on the major cardiac VGCs, including hNav 1...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29331839/functional-characterization-of-a-novel-herg-variant-in-a-family-with-recurrent-sudden-infant-death-syndrome-retracting-a-genetic-diagnosis
#11
Valentine Sergeev, Frances Perry, Thomas M Roston, Shubhayan Sanatani, Glen F Tibbits, Thomas W Claydon
Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2...
March 2018: Forensic Science International
https://www.readbyqxmd.com/read/29297274/development-of-models-for-predicting-torsade-de-pointes-cardiac-arrhythmias-using-perceptron-neural-networks
#12
Mohsen Sharifi, Dan Buzatu, Stephen Harris, Jon Wilkes
BACKGROUND: Blockage of some ion channels and in particular, the hERG (human Ether-a'-go-go-Related Gene) cardiac potassium channel delays cardiac repolarization and can induce arrhythmia. In some cases it leads to a potentially life-threatening arrhythmia known as Torsade de Pointes (TdP). Therefore recognizing drugs with TdP risk is essential. Candidate drugs that are determined not to cause cardiac ion channel blockage are more likely to pass successfully through clinical phases II and III trials (and preclinical work) and not be withdrawn even later from the marketplace due to cardiotoxic effects...
December 28, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/29274816/molecular-determinants-of-loperamide-and-n-desmethyl-loperamide-binding-in-the-herg-cardiac-k-channel
#13
Roy J Vaz, Jiesheng Kang, Yongyi Luo, David Rampe
Abuse of the common anti-diarrheal loperamide is associated with QT interval prolongation as well as development of the potentially fatal arrhythmia torsades de pointes. The mechanism underlying this cardiotoxicity is high affinity inhibition of the human ether-a-go-go-related gene (hERG) cardiac K+ channel. N-Desmethyl loperamide is the major metabolite of loperamide and is a close structural relative of the parent molecule. To date no information is available regarding the affinity of N-desmethyl loperamide for human cardiac ion channels...
December 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29203397/pro-arrhythmic-effects-of-low-plasma-k-in-human-ventricle-an-illustrated-review
#14
REVIEW
Beatriz Trenor, Karen Cardona, Lucia Romero, Juan F Gomez, Javier Saiz, Sridharan Rajamani, Luiz Belardinelli, Wayne Giles
Potassium levels in the plasma, [K+ ]o , are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e...
November 24, 2017: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29184497/novel-two-step-classifier-for-torsades-de-pointes-risk-stratification-from-direct-features
#15
Jaimit Parikh, Viatcheslav Gurev, John J Rice
While pre-clinical Torsades de Pointes (TdP) risk classifiers had initially been based on drug-induced block of hERG potassium channels, it is now well established that improved risk prediction can be achieved by considering block of non-hERG ion channels. The current multi-channel TdP classifiers can be categorized into two classes. First, the classifiers that take as input the values of drug-induced block of ion channels (direct features). Second, the classifiers that are built on features extracted from output of the drug-induced multi-channel blockage simulations in the in-silico models (derived features)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29181593/real-patient-and-its-virtual-twin-application-of-quantitative-systems-toxicology-modelling-in-the-cardiac-safety-assessment-of-citalopram
#16
Nikunjkumar Patel, Barbara Wiśniowska, Masoud Jamei, Sebastian Polak
A quantitative systems toxicology (QST) model for citalopram was established to simulate, in silico, a 'virtual twin' of a real patient to predict the occurrence of cardiotoxic events previously reported in patients under various clinical conditions. The QST model considers the effects of citalopram and its most notable electrophysiologically active primary (desmethylcitalopram) and secondary (didesmethylcitalopram) metabolites, on cardiac electrophysiology. The in vitro cardiac ion channel current inhibition data was coupled with the biophysically detailed model of human cardiac electrophysiology to investigate the impact of (i) the inhibition of multiple ion currents (IKr , IKs , ICaL ); (ii) the inclusion of metabolites in the QST model; and (iii) unbound or total plasma as the operating drug concentration, in predicting clinically observed QT prolongation...
November 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29163220/evaluation-of-optogenetic-electrophysiology-tools-in-human-stem-cell-derived-cardiomyocytes
#17
Susann Björk, Elina A Ojala, Tommy Nordström, Antti Ahola, Mikko Liljeström, Jari Hyttinen, Esko Kankuri, Eero Mervaala
Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29156380/structure-based-design-of-herg-neutral-antihypertensive-oxazalone-and-imidazolone-derivatives
#18
Busecan Aksoydan, Isik Kantarcioglu, Ismail Erol, Ramin Ekhteiari Salmas, Serdar Durdagi
Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor...
October 18, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29089383/herg1a-and-herg1b-potassium-channel-subunits-directly-interact-and-preferentially-form-heteromeric-channels
#19
Beth A McNally, Zeus D Pendon, Matthew C Trudeau
Voltage-activated human ether-á-go-go-related gene (hERG) potassium channels are critical for the repolarization of cardiac action potentials and tune-spike frequency adaptation in neurons. Two isoforms of mammalian ERG1 channel subunits, ERG1a and ERG1b, are the principal subunits that conduct the IKr current in the heart and are also broadly expressed in the nervous system. However, there is little direct evidence that ERG1a and ERG1b form heteromeric channels. Here, using electrophysiology, biochemistry, and fluorescence approaches, we systematically tested for direct interactions between hERG1a and hERG1b subunits...
December 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28992755/drug-mediated-shortening-of-action-potentials-in-lqts2-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#20
Gary Duncan, Karl Firth, Vinoj George, Minh Duc Hoang, Andrew Staniforth, Godfrey Smith, Chris Denning
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modeling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarizing potassium current in CMs...
December 1, 2017: Stem Cells and Development
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