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https://www.readbyqxmd.com/read/29055952/aloe-emodin-relieves-high-fat-diet-induced-qt-prolongation-via-mir-1-inhibition-and-ik1-up-regulation-in-rats
#1
Yan Bai, Zhenli Su, Hanqi Sun, Wei Zhao, Xue Chen, Pengzhou Hang, Wenliang Zhu, Zhimin Du
BACKGROUND/AIMS: High-fat diet (HFD) causes cardiac electrical remodeling and increases the risk of ventricular arrhythmias. Aloe-emodin (AE) is an anthraquinone component isolated from rhubarb and has a similar chemical structure with emodin. The protective effect of emodin against cardiac diseases has been reported in the literature. However, the cardioprotective property of AE is still unknown. The present study investigated the effect of AE on HFD-induced QT prolongation in rats. METHODS: Adult male Wistar rats were randomly divided into three groups: control, HFD, and AE-treatment groups...
October 20, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29021306/characterization-of-a-human-induced-pluripotent-stem-cell-derived-cardiomyocyte-model-for-the-study-of-variant-pathogenicity-validation-of-a-kcnj2-mutation
#2
Roselle Gélinas, Nabil El Khoury, Marie-A Chaix, Claudine Beauchamp, Azadeh Alikashani, Nathalie Ethier, Gabrielle Boucher, Louis Villeneuve, Laura Robb, Frédéric Latour, Blandine Mondesert, Lena Rivard, Philippe Goyette, Mario Talajic, Céline Fiset, John David Rioux
BACKGROUND: Long-QT syndrome is a potentially fatal condition for which 30% of patients are without a genetically confirmed diagnosis. Rapid identification of causal mutations is thus a priority to avoid at-risk situations that can lead to fatal cardiac events. Massively parallel sequencing technologies are useful for the identification of sequence variants; however, electrophysiological testing of newly identified variants is crucial to demonstrate causality. Long-QT syndrome could, therefore, benefit from having a standardized platform for functional characterization of candidate variants in the physiological context of human cardiomyocytes...
October 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/29020060/phosphatidylinositol-4-5-bisphosphate-is-required-for-kcnq1-kcne1-channel-function-but-not-anterograde-trafficking
#3
Alice A Royal, Andrew Tinker, Stephen C Harmer
The slow delayed-rectifier potassium current (IKs) is crucial for human cardiac action potential repolarization. The formation of IKs requires co-assembly of the KCNQ1 α-subunit and KCNE1 β-subunit, and mutations in either of these subunits can lead to hereditary long QT syndrome types 1 and 5, respectively. It is widely recognised that the KCNQ1/KCNE1 (Q1/E1) channel requires phosphatidylinositol-4,5-bisphosphate (PIP2) binding for function. We previously identified a cluster of basic residues in the proximal C-terminus of KCNQ1 that form a PIP2/phosphoinositide binding site...
2017: PloS One
https://www.readbyqxmd.com/read/29018970/andersen-s-syndrome-mutants-produce-a-knockdown-of-inwardly-rectifying-k-channel-in-mouse-skeletal-muscle-in-vivo
#4
Dina Simkin, Gaëlle Robin, Serena Giuliano, Ana Vukolic, Pamela Moceri, Nicolas Guy, Kay-Dietrich Wagner, Alain Lacampagne, Bruno Allard, Saïd Bendahhou
Andersen's syndrome (AS) is a rare autosomal disorder that has been defined by the triad of periodic paralysis, cardiac arrhythmia, and developmental anomalies. AS has been directly linked to over 40 different autosomal dominant negative loss-of-function mutations in the KCNJ2 gene, encoding for the tetrameric strong inward rectifying K(+) channel KIR2.1. While KIR2.1 channels have been suggested to contribute to setting the resting membrane potential (RMP) and to control the duration of the action potential (AP) in skeletal and cardiac muscle, the mechanism by which AS mutations produce such complex pathophysiological symptoms is poorly understood...
October 10, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/29017447/characterization-of-a-novel-kcnj2-sequence-variant-detected-in-andersen-tawil-syndrome-patients
#5
Stefanie Scheiper, Brigitte Hertel, Britt-Maria Beckmann, Stefan Kääb, Gerhard Thiel, Silke Kauferstein
BACKGROUND: Mutations in the KCNJ2 gene encoding the ion channel Kir2.1 have been linked to the Andersen-Tawil syndrome (ATS). Molecular genetic screening performed in a family exhibiting clinical ATS phenotypes unmasked a novel sequence variant (c.434A > G, p.Y145C) in this gene. The aim of this study was to investigate the effect of this variant on Kir2.1 ion channel functionality. METHODS: Mutant as well as wild type GFP tagged Kir2.1 channels were expressed in HEK293 cells...
October 10, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28957802/overexpression-of-m3-muscarinic-receptor-suppressed-adverse-electrical-remodeling-in-hypertrophic-myocardium-via-increasing-repolarizing-k-currents
#6
Xue Chen, Yan Bai, Hanqi Sun, Zhenli Su, Jing Guo, Chuan Sun, Zhimin Du
BACKGROUND/AIMS: Cardiac hypertrophy (CH) is an adaptive response to diverse cardiovascular conditions, which is accompanied by adverse electrical remodeling manifested as abnormal K+ channel activities. M3 subtype of muscarinic acetylcholine receptor (M3-mAChR) is a novel regulator of cardiac electrical activity. In this study we aim to explore if the overexpression of M3-mAChR could attenuate the adverse electrical remodeling in CH and then uncover its underlying electrophysiological mechanisms...
September 29, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28863819/differential-effects-of-sterols-on-ion-channels-stereospecific-binding-vs-stereospecific-response
#7
Nicolas Barbera, Manuela A A Ayee, Belinda S Akpa, Irena Levitan
Numerous ion channels have been shown to be regulated by the level of membrane cholesterol, but the mechanisms responsible for these effects are still not well understood. The key question in the field is how to discriminate between the contributions of the two central mechanisms that might be responsible for the sensitivity of ion channels to cholesterol: specific sterol-protein interactions or regulation of channels by the bilayer physical properties. Comparative analysis of cholesterol and its isomers on the function of an ion channel is a powerful tool to achieve this goal...
2017: Current Topics in Membranes
https://www.readbyqxmd.com/read/28863816/insights-into-the-molecular-requirements-for-cholesterol-binding-to-ion-channels
#8
Avia Rosenhouse-Dantsker
The concept that cholesterol binds to proteins via specific binding motifs, and thereby modulates their function, has emerged two decades ago. When we recently embarked on studies to uncover the putative binding region(s) of cholesterol in the Kir2.1 channel, we carried out an unbiased approach that combines computational and experimental methods. This approach resulted in the identification of novel cholesterol-binding regions distinct from known cholesterol-binding motifs. In recent years, a plethora of structures of proteins complexed with cholesterol have been determined revealing variegated cholesterol-binding regions that can provide invaluable insights into the prerequisites for cholesterol binding...
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
#9
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
https://www.readbyqxmd.com/read/28812984/modelling-the-effects-of-quinidine-disopyramide-and-e-4031-on-short-qt-syndrome-variant-3-in-the-human-ventricles
#10
Cunjin Luo, Kuanquan Wang, Henggui Zhang
Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current IK1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3...
August 16, 2017: Physiological Measurement
https://www.readbyqxmd.com/read/28749940/upregulation-of-an-inward-rectifying-k-channel-can-rescue-slow-ca2-oscillations-in-k-atp-channel-deficient-pancreatic-islets
#11
Vehpi Yildirim, Suryakiran Vadrevu, Benjamin Thompson, Leslie S Satin, Richard Bertram
Plasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting β-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the β-cell plasma membrane and terminates islet oscillations...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28711067/pa-6-inhibits-inward-rectifier-currents-carried-by-v93i-and-d172n-gain-of-function-kir2-1-channels-but-increases-channel-protein-expression
#12
Yuan Ji, Marlieke G Veldhuis, Jantien Zandvoort, Fee L Romunde, Marien J C Houtman, Karen Duran, Gijs van Haaften, Eva-Maria Zangerl-Plessl, Hiroki Takanari, Anna Stary-Weinzinger, Marcel A G van der Heyden
BACKGROUND: The inward rectifier potassium current IK1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of-function mutations V93I and D172N associate with increased IK1, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC50 = 14 nM with inside-out patch clamp methodology) and specific IK1 inhibitor that interacts with the cytoplasmic pore region of the KIR2...
July 15, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28660286/hydrocinnamic-acid-inhibits-the-currents-of-wt-and-sqt3-syndrome-related-mutants-of-kir2-1-channel
#13
Shuxi Ren, Chunli Pang, Yayue Huang, Chengfen Xing, Yong Zhan, Hailong An
Gain of function in mutations, D172N and E299V, of Kir2.1 will induce type III short QT syndrome. In our previous work, we had identified that a mixture of traditional Chinese medicine, styrax, is a blocker of Kir2.1. Here, we determined a monomer, hydrocinnamic acid (HA), as the effective component from 18 compounds of styrax. Our data show that HA can inhibit the currents of Kir2.1 channel in both excised inside-out and whole-cell patch with the IC50 of 5.21 ± 1.02 and 10.08 ± 0.46 mM, respectively...
October 2017: Journal of Membrane Biology
https://www.readbyqxmd.com/read/28609477/atrial-arrhythmogenicity-of-kcnj2-mutations-in-short-qt-syndrome-insights-from-virtual-human-atria
#14
Dominic G Whittaker, Haibo Ni, Aziza El Harchi, Jules C Hancox, Henggui Zhang
Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2...
June 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28592292/effects-of-amiodarone-on-short-qt-syndrome-variant-3-in-human-ventricles-a-simulation-study
#15
Cunjin Luo, Kuanquan Wang, Henggui Zhang
BACKGROUND: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS...
June 7, 2017: Biomedical Engineering Online
https://www.readbyqxmd.com/read/28543529/kir2-1-and-k2p1-channels-reconstitute-two-levels-of-resting-membrane-potential-in-cardiomyocytes
#16
Dongchuan Zuo, Kuihao Chen, Min Zhou, Zheng Liu, Haijun Chen
KEY POINTS: Outward and inward background currents across the cell membrane balance, determining resting membrane potential. Inward rectifier K(+) channel subfamily 2 (Kir2) channels primarily maintain the resting membrane potential of cardiomyocytes. Human cardiomyocytes exhibit two levels of resting membrane potential at subphysiological extracellular K(+) concentrations or pathological hypokalaemia, however, the underlying mechanism is unclear. In the present study, we show that human cardiomyocytes derived from induced pluripotent stem cells with enhanced expression of isoform 1 of Kir2 (Kir2...
August 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28542320/the-ik1-kir2-1-channel-agonist-zacopride-prevents-and-cures-acute-ischemic-arrhythmias-in-the-rat
#17
Xu-Wen Zhai, Li Zhang, Yun-Fei Guo, Ying Yang, Dong-Ming Wang, Yan Zhang, Pan Li, Yi-Fan Niu, Qi-Long Feng, Bo-Wei Wu, Ji-Min Cao, Qing-Hua Liu
Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery...
2017: PloS One
https://www.readbyqxmd.com/read/28452394/hierarchical-organization-and-genetically-separable-subfamilies-of-psd95-postsynaptic-supercomplexes
#18
René A W Frank, Fei Zhu, Noboru H Komiyama, Seth G N Grant
PSD95 is an abundant postsynaptic scaffold protein in glutamatergic synapses that assembles into supercomplexes composed of over 80 proteins including neurotransmitter receptors, ion channels and adhesion proteins. How these diverse constituents are organized into PSD95 supercomplexes in vivo is poorly understood. Here, we dissected the supercomplexes in mice combining endogenous gene-tagging, targeted mutations and quantitative biochemical assays. Generating compound heterozygous mice with two different gene-tags, one on each Psd95 allele, showed that each ~1...
August 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28446610/conformational-changes-at-cytoplasmic-intersubunit-interactions-control-kir-channel-gating
#19
COMPARATIVE STUDY
Shizhen Wang, William F Borschel, Sarah Heyman, Phillip Hsu, Colin G Nichols
The defining structural feature of inward-rectifier potassium (Kir) channels is the unique Kir cytoplasmic domain. Recently we showed that salt bridges located at the cytoplasmic domain subunit interfaces (CD-Is) of eukaryotic Kir channels control channel gating via stability of a novel inactivated closed state. The cytoplasmic domains of prokaryotic and eukaryotic Kir channels show similar conformational rearrangements to the common gating ligand, phosphatidylinositol bisphosphate (PIP2), although these exhibit opposite coupling to opening and closing transitions...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28432059/increased-amplitude-of-inward-rectifier-k-currents-with-advanced-age-in-smooth-muscle-cells-of-murine-superior-epigastric-arteries
#20
Sebastien Hayoz, Jessica Pettis, Vanessa Bradley, Steven S Segal, William F Jackson
Inward rectifier K(+) channels (KIR) may contribute to skeletal muscle blood flow regulation and adapt to advanced age. Using mouse abdominal wall superior epigastric arteries (SEAs) from either young (3-6 mo) or old (24-26 mo) male C57BL/6 mice, we investigated whether SEA smooth muscle cells (SMCs) express functional KIR channels and how aging may affect KIR function. Freshly dissected SEAs were either enzymatically dissociated to isolate SMCs for electrophysiological recording (perforated patch) and mRNA expression or used intact for pressure myography...
June 1, 2017: American Journal of Physiology. Heart and Circulatory Physiology
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