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https://www.readbyqxmd.com/read/28216048/chloroquine-blocks-the-kir4-1-channels-by-an-open-pore-blocking-mechanism
#1
Leticia G Marmolejo-Murillo, Iván A Aréchiga-Figueroa, Eloy G Moreno-Galindo, Ricardo A Navarro-Polanco, Aldo A Rodríguez-Menchaca, Meng Cui, José A Sánchez-Chapula, Tania Ferrer
Kir4.1 channels have been implicated in various physiological processes, mainly in the K(+) homeostasis of the central nervous system and in the control of glial function and neuronal excitability. Even though, pharmacological research of these channels is very limited. Chloroquine (CQ) is an amino quinolone derivative known to inhibit Kir2.1 and Kir6.2 channels with different action mechanism and binding site. Here, we employed patch-clamp methods, mutagenesis analysis, and molecular modeling to characterize the molecular pharmacology of Kir4...
February 16, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28188270/dual-mechanism-for-inhibition-of-inwardly-rectifying-kir2-x-channels-by-quinidine-involving-direct-pore-block-and-pip2-interference
#2
Christoph Koepple, Daniel Scherer, Claudia Seyler, Eberhard Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies IK1 current. While a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild type and mutant Kir2...
February 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28148533/inhibition-of-vascular-smooth-muscle-inward-rectifier-k-channels-restores-myogenic-tone-in-mouse-urinary-bladder-arterioles
#3
Nathan R Tykocki, Adrian D Bonev, Thomas Andrew Longden, Thomas J Heppner, Mark T Nelson
Prolonged decreases in urinary bladder blood flow are linked to overactive and underactive bladder pathologies. However, the mechanisms regulating bladder vascular reactivity are largely unknown. To investigate these mechanisms, we examined myogenic and vasoactive properties of mouse bladder feed arterioles (BFAs). Unlike similar-sized arterioles from other vascular beds, BFAs failed to constrict in response to increases in intraluminal pressure (5-80 mmHg). Consistent with this lack of myogenic tone, arteriolar smooth muscle cell membrane potential was hyperpolarized (-72...
February 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28131627/down-regulation-of-kir2-6-channel-by-c-termini-mutation-d252n-and-its-association-with-the-susceptibility-to-thyrotoxic-periodic-paralysis
#4
Rolf Matias Paninka, Estevão Carlos-Lima, Susan C Lindsey, Ilda S Kunii, Magnus R Dias-da-Silva, Manoel Arcisio-Miranda
Inward rectifying potassium - Kir - channels drive the resting potential to potassium reversal potential and, when disrupted, might be related to muscular diseases. Recently, Thyrotoxic Periodic Paralysis (TPP) has emerged as a channelopathy related to mutations in KCNJ18 gene, which encodes Kir2.6 channel. TPP is a neuromuscular disorder characterized by a triad of muscle weakness, hypokalemia, and thyrotoxicosis, the latter being essential for the crisis. Direct sequencing revealed two heterozygous mutations - D252N and R386C - in two TPP patients...
January 25, 2017: Neuroscience
https://www.readbyqxmd.com/read/28112313/soluble-epoxide-hydrolase-inhibitors-might-prevent-ischemic-arrhythmias-via-microrna-1-repression-in-primary-neonatal-mouse-ventricular-myocytes
#5
Qiong Liu, Xuan Zhao, Ran Peng, Mi Wang, Wang Zhao, Ya-Jun Gui, Cai-Xiu Liao, Dan-Yan Xu
Ischemic arrhythmias are the main causes of sudden cardiac death. It has been reported that soluble epoxide hydrolase inhibitors (sEHis) could prevent arrhythmias; however, the underlying molecular mechanisms remain unclear. In recent years, the proarrhythmic role of microRNA-1 (miR-1) has been investigated. This study aimed to elucidate whether sEHis prevented ischemic arrhythmias by suppressing miR-1. The primary neonatal mouse ventricular myocyte model of miR-1 overexpression was established by incubating with agonist microONTM mmu-miR-1a-3p agomir (DAEDstain(TM) Dye) (agomiR-1)...
January 23, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28007664/effects-of-seasonal-acclimatization-on-action-potentials-and-sarcolemmal-k-currents-in-roach-rutilus-rutilus-cardiac-myocytes
#6
Ahmed Badr, Minna Hassinen, Mohamed F El-Sayed, Matti Vornanen
Temperature sensitivity of electrical excitability is a potential limiting factor for high temperature tolerance of ectotherms. The present study examines whether heat resistance of electrical excitability of cardiac myocytes is modified by seasonal thermal acclimatization in roach (Rutilus rutilus), a eurythermal teleost species. To this end, temperature dependencies of ventricular action potentials (APs), and atrial and ventricular K(+) currents were measured from winter-acclimatized (WiR) and summer-acclimatized (SuR) roach...
March 2017: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
https://www.readbyqxmd.com/read/28004830/fluid-flow-facilitates-inward-rectifier-k-current-by-convectively-restoring-k-at-the-cell-membrane-surface
#7
Jae Gon Kim, Sang Woong Park, Doyoung Byun, Wahn Soo Choi, Dong Jun Sung, Kyung Chul Shin, Hyun-Ji Kim, Young-Eun Leem, Jong-Sun Kang, Hana Cho, Bokyung Kim, Sung I Cho, Young Min Bae
The inward rectifier Kir2.1 current (IKir2.1) was reported to be facilitated by fluid flow. However, the mechanism underlying this facilitation remains uncertain. We hypothesized that during K(+) influx or efflux, [K(+)] adjacent to the outer mouth of the Kir2.1 channel might decrease or increase, respectively, compared with the average [K(+)] of the bulk extracellular solution, and that fluid flow could restore the original [K(+)] and result in the apparent facilitation of IKir2.1. We recorded the IKir2.1 in RBL-2H3 cells and HEK293T cells that were ectopically over-expressed with Kir2...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27882143/expression-of-connexin-43-ion-channels-and-ca-2-handling-proteins-in-rat-pulmonary-vein-cardiomyocytes
#8
Yaqiong Xiao, Xue Cai, Andrew Atkinson, Sunil Jit Logantha, Mark Boyett, Halina Dobrzynski
Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF is thought to be triggered by ectopic beats, originating primarily in the myocardial sleeves surrounding the pulmonary veins (PVs). The mechanisms underlying these cardiac arrhythmias remain unclear. To investigate this, frozen sections of heart and lung tissue from adult rats without arrhythmia were obtained in different planes, stained with Masson's trichrome, and immunolabeled for connexin 43 (Cx43), caveolin-3 (Cav3), hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), Nav1...
November 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27872214/effects-of-prolonged-anoxia-on-electrical-activity-of-the-heart-in-crucian-carp-carassius-carassius
#9
Elisa Tikkanen, Jaakko Haverinen, Stuart Egginton, Minna Hassinen, Matti Vornanen
The effects of sustained anoxia on cardiac electrical excitability were examined in the anoxia-tolerant crucian carp (Carassius carassius). The electrocardiogram (ECG) and expression of excitation-contraction coupling genes were studied in fish acclimatised to normoxia in summer (+18°C) or winter (+2°C), and in winter fish after 1, 3 and 6 weeks of anoxia. Anoxia induced a sustained bradycardia from a heart rate of 10.3±0.77 beats min(-1) to 4.1±0.29 beats min(-1) (P<0.05) after 5 weeks, and heart rate slowly recovered to control levels when oxygen was restored...
February 1, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/27859264/inwardly-rectifying-k-channels-are-major-contributors-to-flow-induced-vasodilatation-in-resistance-arteries
#10
Sang Joon Ahn, Ibra S Fancher, Jing-Tan Bian, Chong Xu Zhang, Sarah Schwab, Robert Gaffin, Shane A Phillips, Irena Levitan
KEY POINTS: Endothelial inwardly rectifying K(+) (Kir2.1) channels regulate flow-induced vasodilatation via nitric oxide (NO) in mouse mesenteric resistance arteries. Deficiency of Kir2.1 channels results in elevated blood pressure and increased vascular resistance. Flow-induced vasodilatation in human resistance arteries is also regulated by inwardly rectifying K(+) channels. This study presents the first direct evidence that Kir channels play a critical role in physiological endothelial responses to flow...
November 17, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27849039/an-insecticide-resistance-breaking-mosquitocide-targeting-inward-rectifier-potassium-channels-in-vectors-of-zika-virus-and-malaria
#11
Daniel R Swale, Darren W Engers, Sean R Bollinger, Aaron Gross, Edna Alfaro Inocente, Emily Days, Fariba Kanga, Reed M Johnson, Liu Yang, Jeffrey R Bloomquist, Corey R Hopkins, Peter M Piermarini, Jerod S Denton
Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27807980/convergence-and-sampling-in-determining-free-energy-landscapes-for-membrane-protein-association
#12
Jan Domanski, George Hedger, Robert B Best, Phillip James Stansfeld, Mark S P Sansom
Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein-lipid and protein-protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable describing the binding and unbinding transition, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein-lipid binding PMFs for ANT/cardiolipin and Kir2...
November 3, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27789106/reversible-dilated-cardiomyopathy-caused-by-a-high-burden-of-ventricular-arrhythmias-in-andersen-tawil-syndrome
#13
Saman Rezazadeh, Jiqing Guo, Henry J Duff, Raechel A Ferrier, Brenda Gerull
Andersen-Tawil syndrome (ATS) is caused by mutations in KCNJ2 (Kir2.1). It remains unclear whether dilated cardiomyopathy (DCM) is a primary feature of ATS. We studied a proband with typical physical features of ATS plus DCM and moderate to severe left ventricular dysfunction (left ventricular ejection fraction = 30.5%). Genetic screening revealed a novel mutation in Kir2.1 (c.665T>C, p.L222S). Functional studies showed that this mutation reduced ionic currents in a dominant-negative manner. Suppression of ventricular arrhythmias with bisoprolol led to normalization of left ventricular size and function...
July 27, 2016: Canadian Journal of Cardiology
https://www.readbyqxmd.com/read/27762288/the-effects-of-puerarin-on-rat-ventricular-myocytes-and-the-potential-mechanism
#14
Hao Xu, Manxi Zhao, Shenghui Liang, Quanshu Huang, Yunchuan Xiao, Liang Ye, Qinyi Wang, Longmei He, Lanxiang Ma, Hua Zhang, Li Zhang, Hui Jiang, Xiao Ke, Yuchun Gu
Puerarin, a known isoflavone, is commonly found as a Chinese herb medicine. It is widely used in China to treat cardiac diseases such as angina, cardiac infarction and arrhythmia. However, its cardioprotective mechanism remains unclear. In this study, puerarin significantly prolonged ventricular action potential duration (APD) with a dosage dependent manner in the micromolar range on isolated rat ventricular myocytes. However, submicromolar puerarin had no effect on resting membrane potential (RMP), action potential amplitude (APA) and maximal velocity of depolarization (Vmax) of action potential...
October 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27751963/inward-rectifying-k-kir2-leak-conductance-dampens-the-excitability-of-lamina-i-projection-neurons-in-the-neonatal-rat
#15
Neil C Ford, Mark L Baccei
Spinal lamina I projection neurons serve as a major conduit by which noxious stimuli detected in the periphery are transmitted to nociceptive circuits in the brain, including the parabrachial nucleus (PB) and the periaqueductal gray (PAG). While neonatal spino-PB neurons are more than twice as likely to exhibit spontaneous activity compared to spino-PAG neurons, the underlying mechanisms remain unclear since nothing is known about the voltage-independent (i.e. 'leak') ion channels expressed by these distinct populations during early life...
December 17, 2016: Neuroscience
https://www.readbyqxmd.com/read/27747100/altered-left-ventricular-ion-channel-transcriptome-in-a-high-fat-fed-rat-model-of-obesity-insight-into-obesity-induced-arrhythmogenesis
#16
Reza Ashrafi, Marianne Yon, Lucy Pickavance, Joseph Yanni Gerges, Gershan Davis, John Wilding, Kun Jian, Henggui Zhang, George Hart, Mark Boyett
Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (n = 8). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR...
2016: Journal of Obesity
https://www.readbyqxmd.com/read/27699887/three-pairs-of-weak-interactions-precisely-regulate-the-g-loop-gate-of-kir2-1-channel
#17
Junwei Li, Shaoying Xiao, Xiaoxiao Xie, Hui Zhou, Chunli Pang, Shanshan Li, Hailin Zhang, Diomedes E Logothetis, Yong Zhan, Hailong An
Kir2.1 (also known as IRK1) plays key roles in regulation of resting membrane potential and cell excitability. To achieve its physiological roles, Kir2.1 performs a series of conformational transition, named as gating. However, the structural basis of gating is still obscure. Here, we combined site-directed mutation, two-electrode voltage clamp with molecular dynamics simulations and determined that H221 regulates the gating process of Kir2.1 by involving a weak interaction network. Our data show that the H221R mutant accelerates the rundown kinetics and decelerates the reactivation kinetics of Kir2...
December 2016: Proteins
https://www.readbyqxmd.com/read/27696527/differential-kv1-3-kca3-1-and-kir2-1-expression-in-classically-and-alternatively-activated-microglia
#18
Hai M Nguyen, Eva M Grössinger, Makoto Horiuchi, Kyle W Davis, Lee-Way Jin, Izumi Maezawa, Heike Wulff
Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-γ (IFN-γ) promote differentiation into classically activated M1-like microglia, which produce high levels of pro-inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL-4 in contrast induces a phenotype associated with anti-inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K(+) channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL-4) microglia and studying their K(+) channel expression by whole-cell patch-clamp, quantitative PCR and immunohistochemistry...
January 2017: Glia
https://www.readbyqxmd.com/read/27598576/mechanisms-underlying-interferon-%C3%AE-induced-priming-of-microglial-reactive-oxygen-species-production
#19
Nicholas G Spencer, Tom Schilling, Francesc Miralles, Claudia Eder
Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME...
2016: PloS One
https://www.readbyqxmd.com/read/27560040/decreased-inward-rectifier-potassium-current-ik1-in-dystrophin-deficient-ventricular-cardiomyocytes
#20
Lena Rubi, Xaver Koenig, Helmut Kubista, Hannes Todt, Karlheinz Hilber
Kir2.x channels in ventricular cardiomyocytes (most prominently Kir2.1) account for the inward rectifier potassium current IK1, which controls the resting membrane potential and the final phase of action potential repolarization. Recently it was hypothesized that the dystrophin-associated protein complex (DAPC) is important in the regulation of Kir2.x channels. To test this hypothesis, we investigated potential IK1 abnormalities in dystrophin-deficient ventricular cardiomyocytes derived from the hearts of Duchenne muscular dystrophy mouse models...
August 25, 2016: Channels
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