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https://www.readbyqxmd.com/read/29311306/mechanism-specific-assay-design-facilitates-the-discovery-of-nav1-7-selective-inhibitors
#1
Tania Chernov-Rogan, Tianbo Li, Gang Lu, Henry Verschoof, Kuldip Khakh, Steven W Jones, Maureen H Beresini, Chang Liu, Daniel F Ortwine, Steven J McKerrall, David H Hackos, Daniel Sutherlin, Charles J Cohen, Jun Chen
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29306897/critical-roles-of-xirp-proteins-in-cardiac-conduction-and-their-rare-variants-identified-in-sudden-unexplained-nocturnal-death-syndrome-and-brugada-syndrome-in-chinese-han-population
#2
Lei Huang, Kuo-Ho Wu, Liyong Zhang, Qinchuan Wang, Shuangbo Tang, Qiuping Wu, Pei-Hsiu Jiang, Jim Jung-Ching Lin, Jian Guo, Lin Wang, Shih-Hurng Loh, Jianding Cheng
BACKGROUND: Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy-associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc-associated, Xin repeats-containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization...
January 6, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29258373/kv1-3-a-multifunctional-channel-with-many-pathological-implications
#3
Antonio Serrano-Albarrás, Irene Estadella, Sergi Cirera-Rocosa, María Navarro-Pérez, Antonio Felipe
No abstract text is available yet for this article.
December 20, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29209776/hyperoxia-induced-cardiotoxicity-and-ventricular-remodeling-in-type-ii-diabetes-mice
#4
Jennifer Leigh Rodgers, Eva Samal, Subhra Mohapatra, Siva Kumar Panguluri
Hyperoxia, or supplemental oxygen, is regularly used in the clinical setting for critically ill patients in ICU. However, several recent studies have demonstrated the negative impact of this treatment in patients in critical care, including increased rates of lung and cardiac injury, as well as increased mortality. The purpose of this study was to determine the predisposition for arrhythmias and electrical remodeling in a type 2 diabetic mouse model (db/db), as a result of hyperoxia treatment. For this, db/db and their heterozygous controls were treated with hyperoxia (> 90% oxygen) or normoxia (normal air) for 72-h...
December 5, 2017: Heart and Vessels
https://www.readbyqxmd.com/read/29186963/molecular-epidemiology-and-genetic-diversity-of-duck-hepatitis-a-virus-type-3-in-shandong-province-of-china-2012-2014
#5
R Zhang, L Xia, J Chen, Y Gong, L Zhang, P Li, H Liu, Z Xie, S Jiang
 The infections with duck hepatitis A virus type 3 (DHAV-3) become common in eastern Asia. To better understand the molecular evolution and genetic variation of DHAV-3, a total of 482 dead Cherry Valley duckling liver samples collected from Shandong province of China during 2012-2014 were tested, and the complete P1 coding sequences of 18 DHAV-3 strains were analyzed. The detection rate of DHAV-3 was 64.5% (311/482) in clinical liver samples and 73.0% (92/126) in duckling flocks. The P1 genes of the 18 DHAV-3 isolates shared 91...
2017: Acta Virologica
https://www.readbyqxmd.com/read/29172176/atp-sensitive-and-maxi-potassium-channels-regulate-brl-37344-induced-tocolysis-in-buffaloes-an-in%C3%A2-vitro-study
#6
Vipin Sharma, Sooraj V Nair, Pooja Jaitley, Udayraj P Nakade, Abhishek Sharma, Soumen Choudhury, Satish Kumar Garg
Cellular coupling of beta3-adrenoceptors (β3-ADR) to potassium channels in myometrium is largely unknown. In vitro study was undertaken to unravel the presence of β3-adrenergic receptors (ADR) and the role of K(+)-channels in mediating β3-ADR-induced relaxation in isolated myometrial strips from cyclic non-pregnant water buffaloes. Isometric tension was recorded in isolated myometrial strips using data acquisition system based physiograph. Compared to SR 59230A, BRL 37344 was found to be more potent in inducing β3-dependent myometrial relaxation which was significantly (p < 0...
November 13, 2017: Theriogenology
https://www.readbyqxmd.com/read/29168928/regulation-of-kv1-4-potassium-channels-by-pkc-and-ampk-kinases
#7
Martin Nybo Andersen, Lasse Skibsbye, Arnela Saljic, Martin Zahle Larsen, Hanne Borger Rasmussen, Thomas Jespersen
Over the last years extensive kinase-mediated regulation of a number of voltage-gated potassium (Kv) channels important in cardiac electrophysiology has been reported. This includes regulation of Kv1.5, Kv7.1 and Kv11.1 cell surface expression, where the kinase-mediated regulation appears to center around the ubiquitin ligase Nedd4-2. In the present study we examined whether Kv1.4, constituting the cardiac Ito,s current, is subject to similar regulation. In the epithelial Madin-Darby Canine Kidney (MDCK) cell line, which constitutes a highly reproducible model system for addressing membrane targeting, we find, by confocal microscopy, that Kv1...
November 23, 2017: Channels
https://www.readbyqxmd.com/read/29142737/cloning-expression-and-identification-of-ktx-sp4-a-selective-kv1-3-peptidic-blocker-from-scorpiops-pococki
#8
Yan Zou, Feng Zhang, Yaxian Li, Yuanfang Wang, Yi Li, Zhengtao Long, Shujuan Shi, Li Shuai, Jiukai Liu, Zhiyong Di, Shijin Yin
Background: Specific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors. Through conducting transcriptomic sequencing for the venom gland of Scorpiops pococki from Xizang province of China, this research aims to discover a novel functional gene encoding peptidic blocker of Kv1.3, and identify its function. Results: We screened out a new peptide toxin KTX-Sp4 which had 43 amino acids including six cysteine residues...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/29139549/elevated-potassium-outward-currents-in-hyperoxia-treated-atrial-cardiomyocytes
#9
Z Vysotskaya, B Chidipi, J L Rodgers, X Tang, E Samal, N Kolliputi, S Mohapatra, E S Bennett, S K Panguluri
Supplementation of 100% oxygen is a very common intervention in intensive care units (ICU) and critical care centers for patients with dysfunctional lung and lung disorders. Although there is advantage in delivering sufficient levels of oxygen, hyperoxia is reported to be directly associated with increasing in-hospital deaths. Our previous studies reported ventricular and electrical remodeling in hyperoxia treated mouse hearts, and in this article, for the first time, we are investigating the effects of hyperoxia on atrial electrophysiology using whole-cell patch-clamp electrophysiology experiments along with assessment of Kv1...
November 15, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29131061/kinetic-aspects-of-verapamil-binding-on-rate-on-wild-type-and-six-hkv1-3-mutant-channels
#10
Ann-Kathrin Diesch, Stephan Grissmer
BACKGROUND/AIMS: The human-voltage gated Kv1.3 channel (hKv1.3) is expressed in T- and B lymphocytes. Verapamil is able to block hKv1.3 channels. We characterized the effect of verapamil on currents through hKv1.3 channels paying special attention to the on-rate (kon) of verapamil. By comparing on-rates obtained in wild-type (wt) and mutant channels a binding pocket for verapamil and impacts of different amino acid residues should be investigated. METHODS: Using the whole-cell patch clamp technique the action of verapamil on currents through wild-type and six hKv1...
November 6, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29034212/regulation-of-proliferation-by-a-mitochondrial-potassium-channel-in-pancreatic-ductal-adenocarcinoma-cells
#11
Roberta Peruzzo, Andrea Mattarei, Matteo Romio, Cristina Paradisi, Mario Zoratti, Ildikò Szabò, Luigi Leanza
Previous results link the mitochondrial potassium channel Kv1.3 (mitoKv1.3) to the regulation of apoptosis. By synthesizing new, mitochondria-targeted derivatives (PAPTP and PCARBTP) of PAP-1, a specific membrane-permeant Kv1.3 inhibitor, we have recently provided evidence that both drugs acting on mitoKv1.3 are able to induce apoptosis and reduce tumor growth in vivo without affecting healthy tissues and cells. In the present article, by exploiting these new drugs, we addressed the question whether mitoKv1...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29018452/kv1-3-channel-blockade-modulates-the-effector-function-of-b-cells-in-granulomatosis-with-polyangiitis
#12
Judith Land, Lucas L Lintermans, Coen A Stegeman, Ernesto J Muñoz-Elías, Eric J Tarcha, Shawn P Iadonato, Peter Heeringa, Abraham Rutgers, Wayel H Abdulahad
B cells are central to the pathogenesis of granulomatosis with polyangiitis (GPA), exhibiting both (auto)antibody-dependent and -independent properties. Class-switched memory B cells in particular are a major source of pathogenic autoantibodies. These cells are characterized by high expression levels of Kv1.3 potassium channels, which may offer therapeutic potential for Kv1.3 blockade. In this study, we investigated the effect of the highly potent Kv1.3 blocker ShK-186 on B cell properties in GPA in vitro. Circulating B cell subsets were determined from 33 GPA patients and 17 healthy controls (HCs)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28987271/co-independent-modification-of-k-channels-by-tricarbonyldichlororuthenium-ii-dimer-corm-2
#13
Guido Gessner, Nirakar Sahoo, Sandip M Swain, Gianna Hirth, Roland Schönherr, Ralf Mede, Matthias Westerhausen, Hans Henning Brewitz, Pascal Heimer, Diana Imhof, Toshinori Hoshi, Stefan H Heinemann
Although toxic when inhaled in high concentrations, the gas carbon monoxide (CO) is endogenously produced in mammals, and various beneficial effects are reported. For potential medicinal applications and studying the molecular processes underlying the pharmacological action of CO, so-called CO-releasing molecules (CORMs), such as tricabonyldichlororuthenium(II) dimer (CORM-2), have been developed and widely used. Yet, it is not readily discriminated whether an observed effect of a CORM is caused by the released CO gas, the CORM itself, or any of its intermediate or final breakdown products...
November 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28964116/revealing-kinetics-and-state-dependent-binding-properties-of-ikur-targeting-drugs-that-maximize-atrial-fibrillation-selectivity
#14
Nicholas Ellinwood, Dobromir Dobrev, Stefano Morotti, Eleonora Grandi
The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects...
September 2017: Chaos
https://www.readbyqxmd.com/read/28962142/effects-of-selenium-on-myocardial-apoptosis-by-modifying-the-activity-of-mitochondrial-stat3-and-regulating-potassium-channel-expression
#15
Changjiang Zhang, Yinzhi Deng, Yuhua Lei, Jingbo Zhao, Wen Wei, Yuanhong Li
The present study investigated the effects of myocardial mitochondrial signal transduction and activator of transcription 3 (STAT3), succinate dehydrogenase activity and changes of potassium channel expression on cardiomyocyte apoptosis under low selenium conditions. Primary cultured cardiomyocytes from neonatal mice were divided into the non-toxic control group (0.1 µM sodium selenite) and low selenium treatment group (0.05 µM sodium selenite) according to different selenium concentrations. The expression of mitochondrial STAT3, p-STAT3, p-Kv1...
September 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28931540/review-on-the-secret-life-of-ion-channels-kv1-3-potassium-channels-and-cell-proliferation
#16
M Teresa Perez Garcia, Pilar Cidad, Jose R Lopez-Lopez
Kv1.3 channels are involved in the switch to proliferation of normally quiescent cells, being implicated in the control of cell cycle in many different cell types and in many different ways. They modulate membrane potential controlling K(+) fluxes, sense changes in potential and interact with many signaling molecules through their intracellular domains. From a mechanistic point of view, we can describe the role of Kv1.3 channels in proliferation with at least three different models. In the "membrane potential model", membrane hyperpolarization resulting from Kv1...
September 20, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28888365/functional-reconstitution-of-cell-free-synthesized-purified-kv-channels
#17
Stéphane Renauld, Sandra Cortes, Beate Bersch, Xavier Henry, Michel De Waard, Béatrice Schaack
The study of ion channel activity and the screening of possible inhibitor molecules require reliable methods for production of active channel proteins, their insertion into artificial membranes and for the measurement of their activity. Here we report on cell-free expression of soluble and active Kv1.1 and Kv1.3 channels and their efficient insertion into liposomes. Two complementary methods for the determination of the electrical activity of the proteoliposome-embedded channels were compared using Kv1.1 as a model system: (1) single channel recordings in droplet interface bilayers (DIB) and (2) measurement of the membrane voltage potential generated by a potassium ion diffusion potential using the voltage-sensitive fluorescent dye oxonol VI...
December 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28869943/targeting-the-potassium-channel-kv1-3-kills-glioblastoma-cells
#18
Elisa Venturini, Luigi Leanza, Michele Azzolini, Stephanie Kadow, Andrea Mattarei, Michael Weller, Ghazaleh Tabatabai, Michael J Edwards, Mario Zoratti, Cristina Paradisi, Ildikò Szabò, Erich Gulbins, Katrin Anne Becker
BACKGROUND/AIMS: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells...
September 1, 2017: Neuro-Signals
https://www.readbyqxmd.com/read/28863820/sterol-regulation-of-voltage-gated-k-channels
#19
Andras Balajthy, Peter Hajdu, Gyorgy Panyi, Zoltan Varga
Cholesterol is an essential lipid building block of the cellular plasma membrane. In addition to its structural role, it regulates the fluidity and raft structure of the membrane and influences the course of numerous membrane-linked signaling pathways and the function of transmembrane proteins, including ion channels. This is supported by a vast body of scientific data, which demonstrates the modulation of ion channels with a great variety of ion selectivity, gating, and tissue distribution by changes in membrane cholesterol...
2017: Current Topics in Membranes
https://www.readbyqxmd.com/read/28830445/responses-of-rat-and-mouse-primary-microglia-to-pro-and-anti-inflammatory-stimuli-molecular-profiles-k-channels-and-migration
#20
Doris Lam, Starlee Lively, Lyanne C Schlichter
BACKGROUND: Acute CNS damage is commonly studied using rat and mouse models, but increasingly, molecular analysis is finding species differences that might affect the ability to translate findings to humans. Microglia can undergo complex molecular and functional changes, often studied by in vitro responses to discrete activating stimuli. There is considerable evidence that pro-inflammatory (M1) activation can exacerbate tissue damage, while anti-inflammatory (M2) states help resolve inflammation and promote tissue repair...
August 22, 2017: Journal of Neuroinflammation
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