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https://www.readbyqxmd.com/read/27923051/electrophysiological-characteristics-of-human-ipsc-derived-cardiomyocytes-for-the-assessment-of-drug-induced-proarrhythmic-potential
#1
Wataru Yamamoto, Keiichi Asakura, Hiroyuki Ando, Tomohiko Taniguchi, Atsuko Ojima, Takaaki Uda, Tomoharu Osada, Seiji Hayashi, Chieko Kasai, Norimasa Miyamoto, Hiroyuki Tashibu, Takashi Yoshinaga, Daiju Yamazaki, Atsushi Sugiyama, Yasunari Kanda, Kohei Sawada, Yuko Sekino
The aims of this study were to (1) characterize basic electrophysiological elements of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that correspond to clinical properties such as QT-RR relationship, (2) determine the applicability of QT correction and analysis methods, and (3) determine if and how these in-vitro parameters could be used in risk assessment for adverse drug-induced effects such as Torsades de pointes (TdP). Field potential recordings were obtained from commercially available hiPSC-CMs using multi-electrode array (MEA) platform with and without ion channel antagonists in the recording solution...
2016: PloS One
https://www.readbyqxmd.com/read/27922108/corrigendum-astrocytic-acid-sensing-ion-channel-1a-contributes-to-the-development-of-chronic-epileptogenesis
#2
Feng Yang, Xiaolong Sun, Yinxiu Ding, Hui Ma, Tangpeng Ou Yang, Yue Ma, Dong Wei, Wen Li, Tianle Xu, Wen Jiang
No abstract text is available yet for this article.
December 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27922011/detecting-stoichiometry-of-macromolecular-complexes-in-live-cells-using-fret
#3
Manu Ben-Johny, Daniel N Yue, David T Yue
The stoichiometry of macromolecular interactions is fundamental to cellular signalling yet challenging to detect from living cells. Fluorescence resonance energy transfer (FRET) is a powerful phenomenon for characterizing close-range interactions whereby a donor fluorophore transfers energy to a closely juxtaposed acceptor. Recognizing that FRET measured from the acceptor's perspective reports a related but distinct quantity versus the donor, we utilize the ratiometric comparison of the two to obtain the stoichiometry of a complex...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27920829/clinical-and-genetic-features-of-australian-families-with-long-qt-syndrome-a-registry-based-study
#4
Charlotte Burns, Jodie Ingles, Andrew M Davis, Vanessa Connell, Belinda Gray, Lauren Hunt, Julie McGaughran, Christopher Semsarian
BACKGROUND: Familial long QT syndrome (LQTS) is a primary arrhythmogenic disorder caused by mutations in ion channel genes. The phenotype ranges from asymptomatic individuals to sudden cardiac arrest and death. LQTS is a rare but significant health problem for which global data should exist. This study sought to provide the first clinical and genetic description of Australian families with LQTS. METHODS: We performed a cross-sectional study to evaluate clinical and genetic features of families with LQTS...
December 2016: Journal of Arrhythmia
https://www.readbyqxmd.com/read/27920282/nmda-receptor-encephalitis-and-other-antibody-mediated-disorders-of-the-synapse-the-2016-cotzias-lecture
#5
Josep Dalmau
Investigations during the last 10 years have revealed a group of disorders mediated by antibodies against ion channels and synaptic receptors, which cause both neurologic and psychiatric symptoms. In this review, I discuss the process of discovery and immunologic triggers of these disorders, and use anti-NMDA receptor encephalitis to emphasize the importance of understanding the underlying physiopathologic mechanisms in those diseases. A better knowledge of these mechanisms reveals points of convergence with other disorders (e...
December 6, 2016: Neurology
https://www.readbyqxmd.com/read/27919210/three-dimensional-modelling-of-the-voltage-gated-sodium-ion-channel-from-anopheles-gambiae-reveals-spatial-clustering-of-evolutionarily-conserved-acidic-residues-at-the-extracellular-sites
#6
Rithvik S Vinekar, Ramanathan Sowdhamini
The eukaryotic voltage-gated sodium channel(e-Nav) is a large asymmetric transmembrane protein with important functions concerning neurological function. No structure has been resolved at high resolution for this protein. A homology model of the transmembrane and extracellular regions of an Anopheles gambiae para-like channel with emphasis on the pore entrance has been constructed, based upon the templates provided by a prokaryotic sodium channel and a potassium two-pore channel. The latter provides a template for the extracellular regions, which are located above the entrance to the pore, which is likely to open at a side of a dome formed by these loops...
December 5, 2016: Current Neuropharmacology
https://www.readbyqxmd.com/read/27918599/hierarchical-bayesian-inference-for-ion-channel-screening-dose-response-data
#7
Ross H Johnstone, Rémi Bardenet, David J Gavaghan, Gary R Mirams
Dose-response (or 'concentration-effect') relationships commonly occur in biological and pharmacological systems and are well characterised by Hill curves. These curves are described by an equation with two parameters: the inhibitory concentration 50% (IC50); and the Hill coefficient. Typically just the 'best fit' parameter values are reported in the literature. Here we introduce a Python-based software tool, PyHillFit , and describe the underlying Bayesian inference methods that it uses, to infer probability distributions for these parameters as well as the level of experimental observation noise...
2016: Wellcome Open Res
https://www.readbyqxmd.com/read/27918554/asic1a-mediates-the-drug-resistance-of-human-hepatocellular-carcinoma-via-the-ca-2-pi3-kinase-akt-signaling-pathway
#8
Yihao Zhang, Ting Zhang, Chao Wu, Quan Xia, Dujuan Xu
Chemotherapy is the main treatment method of patients with advanced liver cancer. However, drug resistance is a serious problem in the treatment of hepatocellular carcinoma (HCC). Acid sensing ion channel 1a (ASIC1a) is a H(+)-gated cation channel; it mediates tumor cell migration and invasion, which suggests that it is involved in the development of malignant tumors. Therefore, we studied the relationship between ASIC1a and drug resistance in human hepatocellular carcinoma. In our study, we found that ASIC1a is highly expressed in human HCC tissue, and that its levels were significantly increased in resistant HCC cells Bel7402/FU and HepG2/ADM...
December 5, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27918045/modeling-ion-permeation-through-a-bacterial-voltage-gated-calcium-channel-cavab-using-molecular-dynamics-simulations
#9
Jamal Adiban, Yousef Jamali, Hashem Rafii-Tabar
Activation of voltage-gated calcium channels by action potentials leads to the influx of Ca(2+) ions. In this study, the ion permeation characteristics in bacterial voltage-gated calcium (CaVAb) channels were investigated using molecular dynamics simulations. Furthermore, the potential of mean force (PMF) calculations was evaluated to determine the free energy profile for the permeation of cations (Ca(2+) and Na(+)) and anions (Cl(-)) in the CaVAb channel. The results showed that both Ca(2+) and Na(+) cations experienced a deep energy well, while the Cl(-) anion experienced a relatively high energy barrier at the center of the selectivity filter (site 2)...
December 5, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27917616/effect-of-redox-modifying-agents-on-the-activity-of-channelrhodopsin-2
#10
Bao-Ming Wu, Tian-Dong Leng, Koichi Inoue, Jun Li, Zhi-Gang Xiong
BACKGROUND: The algal protein Channelrhodopsin-2 (ChR2) has been widely used in recent years in optogenetic technique to investigate the functions of complex neuronal networks through minimally invasive and temporally precise photostimulation of genetically defined neurons. However, as with any other new technique, current optogentic approaches have various limitations. In addition, how ChR2 may behave in response to complex biochemical changes associated with various physiological/pathological conditions is largely unknown...
December 4, 2016: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/27917367/the-role-of-interaction-model-in-simulation-of-drug-interactions-and-qt-prolongation
#11
REVIEW
Barbara Wiśniowska, Sebastian Polak
Computational modelling is a cornerstone of Comprehensive In Vitro Proarrhythmia Assay and is re-increasingly being used in drug development. Electrophysiological effects of drug-drug interactions can be predicted in silico, e.g. with the use of in vitro cardiac ion channel data, PK profiles and human ventricular cardiomyocyte models. There are, however, several approaches with different assumptions used to assess the combined effect of multiple drugs, and there is no agreed standard interaction model. The aim of this study was to assess whether the choice of the drug-drug interaction (DDI) model (Bliss independence, Loewe additivity, or simple sum) influences the results of QT interval simulation trial...
2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/27916968/ion-channel-activity-of-vpu-proteins-is-conserved-throughout-evolution-of-hiv-1-and-siv
#12
Timo Greiner, Sebastian Bolduan, Brigitte Hertel, Christine Groß, Kay Hamacher, Ulrich Schubert, Anna Moroni, Gerhard Thiel
The human immunodeficiency virus type 1 (HIV-1) protein Vpu is encoded exclusively by HIV-1 and related simian immunodeficiency viruses (SIVs). The transmembrane domain of the protein has dual functions: it counteracts the human restriction factor tetherin and forms a cation channel. Since these two functions are causally unrelated it remains unclear whether the channel activity has any relevance for viral release and replication. Here we examine structure and function correlates of different Vpu homologs from HIV-1 and SIV to understand if ion channel activity is an evolutionary conserved property of Vpu proteins...
December 1, 2016: Viruses
https://www.readbyqxmd.com/read/27916649/new-horizons-for-cystic-fibrosis-treatment
#13
REVIEW
Isabelle Fajac, Kris De Boeck
Cystic fibrosis is an inherited multi-system disease associated with chronic lung infection, malabsorption, salt loss syndromes, male infertility and leading to numerous comorbidities. The landscape in cystic fibrosis care has changed markedly with currently more adult patients than children in many countries. Over 2000 different mutations in theCFTRgene have been reported and the majority are extremely rare. Understanding howCFTRmutations translate to disturbed synthesis or function of the CFTR protein has opened the way to 'personalized' treatments to correct the basic defect...
December 1, 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27916589/a-novel-mechanism-for-human-cardiac-ankyrin-b-syndrome-due-to-reciprocal-chromosomal-translocation
#14
A J Huq, M D Pertile, A M Davis, H Landon, P A James, C F Kline, J Vohra, P J Mohler, M B Delatycki
BACKGROUND: Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome"). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins. METHODS AND RESULTS: Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B...
November 16, 2016: Heart, Lung & Circulation
https://www.readbyqxmd.com/read/27916567/fluorescent-visualization-of-cellular-proton-fluxes
#15
Lejie Zhang, Karl Bellve, Kevin Fogarty, William R Kobertz
Cells use plasma membrane proton fluxes to maintain cytoplasmic and extracellular pH and to mediate the co-transport of metabolites and ions. Because proton-coupled transport often involves movement of multiple substrates, traditional electrical measurements provide limited information about proton transport at the cell surface. Here we visualize voltage-dependent proton fluxes over the entire landscape of a cell by covalently attaching small-molecule fluorescent pH sensors to the cell's glycocalyx. We found that the extracellularly facing sensors enable real-time detection of proton accumulation and depletion at the plasma membrane, providing an indirect readout of channel and transporter activity that correlated with whole-cell proton current...
November 14, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27916519/structural-basis-of-alcohol-inhibition-of-the-pentameric-ligand-gated-ion-channel-elic
#16
Qiang Chen, Marta M Wells, Tommy S Tillman, Monica N Kinde, Aina Cohen, Yan Xu, Pei Tang
The structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC co-crystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6') and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants...
November 26, 2016: Structure
https://www.readbyqxmd.com/read/27916457/molecular-basis-for-subtype-specificity-and-high-affinity-zinc-inhibition-in-the-glun1-glun2a-nmda-receptor-amino-terminal-domain
#17
Annabel Romero-Hernandez, Noriko Simorowski, Erkan Karakas, Hiro Furukawa
Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure...
November 21, 2016: Neuron
https://www.readbyqxmd.com/read/27914790/sarcoplasmic-reticulum-ca-2-mg-2-k-and-cl-concentrations-adjust-quickly-as-heart-rate-changes
#18
Claudio Berti, Vilmos Zsolnay, Thomas R Shannon, Michael Fill, Dirk Gillespie
During systole, Ca(2+) is released from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs) while, simultaneously, other ions (specifically K(+), Mg(2+), and Cl(-)) provide counter-ion flux. These ions move back into the SR during diastole through the SERCA pump and SR K(+) and Cl(-) channels. In homeostasis, all ion concentrations in different cellular regions (e.g., junctional and non-junctional SR, dyadic cleft, and cytosol) are the same at the beginning and end of the cardiac cycle. Here, we used an equivalent circuit compartment model of the SR and the surrounding cytoplasm to understand the heart rate dependence of SR ion homeostasis...
November 30, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27914061/probing-oligomerized-conformations-of-defensin-in-the-membrane
#19
Wenxun Gan, Dina Schneidman, Ning Zhang, Buyong Ma, Ruth Nussinov
Computational prediction and design of membrane protein-protein interactions facilitate biomedical engineering and biotechnological applications. Due to their antimicrobial activity, human defensins play an important role in the innate immune system. Human defensins are attractive pharmaceutical targets due to their small size, broad activity spectrum, reduced immunogenicity, and resistance to proteolysis. Protein engineering based modification of defensins can improve their pharmaceutical properties. Here we present an approach to computationally probe defensins' oligomerization states in the membrane...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27913935/regulation-of-contractile-responses-of-vascular-smooth-muscle-cells-under-conditions-of-hypoxia-reoxygenation
#20
S V Gusakova, Yu G Birulina, L V Smagliy, I V Kovalev, I V Petrova, A V Nosarev, S N Orlov
We analyzed the effects of hypoxia and reoxygenation on changes in contractile activity in rat aortic smooth muscles. Both hypoxia and reoxygenation induced relaxation of smooth muscle cells precontracted with high-potassium Krebs solution (30 mM KCl) or α1-adrenoceptor agonist phenylephrine. Vasodilation resulted from enhancement of potassium permeability of smooth muscle cell membranes caused by activation of voltage-gated potassium channels (triggered by both precontracting agents) or by opening of ATP-sensitive potassium channels (phenylephrine)...
December 2, 2016: Bulletin of Experimental Biology and Medicine
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