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The Herg Cardiac Potassium Channel
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Book Synopsis The hERG Cardiac Potassium Channel by : Derek J. Chadwick
Download or read book The hERG Cardiac Potassium Channel written by Derek J. Chadwick and published by John Wiley & Sons. This book was released on 2005-06-14 with total page 308 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book draws together contributions from basic, pharmaceutical and clinical sciences aimed at a better understanding of the structure and function of hERG and the molecular basis for compound binding. It features regulatory authority perspectives on preferred preclinical test systems and includes topics on hERG channel gating, regulation of functional expression, pharmacological properties of hERG/IKr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks. Better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias should ultimately lead to the development of important, new and safer medicines.
Book Synopsis Examining the Effects of Activator Compounds on HERG Cardiac Potassium Channel Protective Currents Conducted in Response to Premature Stimulations by : Jacob Kemp
Download or read book Examining the Effects of Activator Compounds on HERG Cardiac Potassium Channel Protective Currents Conducted in Response to Premature Stimulations written by Jacob Kemp and published by . This book was released on 2020 with total page 118 pages. Available in PDF, EPUB and Kindle. Book excerpt: The human ether-a-go-go-related gene (hERG) encodes the rapid delayed rectifier cardiac potassium channel. Vital for repolarization of the myocardium and termination of the cardiac action potential, loss of function in hERG K+ channels can result in Long QT Syndrome Type II (LQTS2). Additionally, hERG channels have been shown to mediate robust repolarizing currents in response to premature depolarizations, reflective of channels remaining in the open state into the refractory period. Thought to be protective against afterdepolarizations, loss of function in this regard may leave individuals susceptible to arrhythmia. Recently, several small molecule activators of hERG have been discovered. The effects of these compounds on the protective currents mediated by hERG channels have yet to be studied. The work presented in this thesis examines the effects of both Type I and II hERG channel activators on protective currents mediated by hERG channels, in the context of an inherited mutation.
Book Synopsis Encyclopedia of Heart Diseases by : M. Gabriel Khan
Download or read book Encyclopedia of Heart Diseases written by M. Gabriel Khan and published by Elsevier. This book was released on 2005-12-14 with total page 678 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Encyclopedia of Heart Diseases is an accurate and reliable source of in-depth information on the diseases that kill more than 12 million individuals worldwide each year. In fact, cardiovascular diseases are more prevalent than the combined incidence of all forms of cancer, diabetes, asthma and leukemia. In one volume, this Encylopedia thoroughly covers these ailments and also includes in-depth analysis of less common and rare heart conditions to round out the volume's scope. Researchers, clinicians, and students alike will all find this resource an invaluable tool for quick reference before approaching the primary literature. * Coverage of more than 200 topics, including: applied pharmacology of current and experimental cardiac drugs, gene therapy, MRI, electron-beam CT, PET scan put in perspective, cardiac tests costs and justification, and new frontiers in cardiovascular research* More than 150 helpful figures and illustrations!* Dr. Khan is a well-published and respected expert in heart and heart diseases
Book Synopsis Cardiac Potassium Channel Herg is Regulated by Ubiquitin Ligase Nedd4-2 by : Heidi Victoria Shallow
Download or read book Cardiac Potassium Channel Herg is Regulated by Ubiquitin Ligase Nedd4-2 written by Heidi Victoria Shallow and published by . This book was released on 2011 with total page 134 pages. Available in PDF, EPUB and Kindle. Book excerpt: The cardiac rapidly activating delayed rectifier potassium channel (IKr) is encoded by the human ether-a-go-go related gene (hERG), which is important for repolarization of the cardiac action potential. Reduction in hERG expression levels due to genetic mutations or drugs causes Long QT Syndrome (LQTS). Recently, we demonstrated that ubiquitination of hERG channels is involved in low K+ induced hERG endocytic degradation. Since homeostatic degradation is an important pathway in maintaining hERG membrane expression levels, we investigated the molecular mechanisms for hERG degradation by focusing on the role and consequence of overexpressing the ubiquitin (Ub) ligase, Nedd4-2 (Neural Precursor Cell- Expressed Developmentally Downregulated Gene 4- 2) (Yang & Kumar, 2010). Previous work in the lab demonstrated that Ub plays a role in the internalization of cell-surface hERG channels, and I hypothesized that ubiquitination of hERG channels is facilitated through Nedd4-2. To study the effects of Nedd4-2 on hERG channels, I overexpressed Nedd4-2 in human embryonic kidney (HEK) 293 cells that stably express the hERG channels. Electrophysiological recordings, Western blot, co-immunoprecipitation analysis, and confocal microscopy were performed to identify Nedd4-2's role in hERG expression. The data from whole-cell patch clamp recordings demonstrated that, among hEAG, Kv1.5 and hERG, Nedd4-2 specifically eliminates the hERG channel current. Western blot and confocal imaging analyses showed that Nedd4-2 overexpression led to a significant reduction in mature hERG channels in the plasma membrane. Data obtained using co-immunoprecipitation indicated that Nedd4-2 significantly increases ubiquitinated hERG channels. These data indicate that Nedd4-2 may play a role in hERG homeostatic degradation.
Book Synopsis Pediatric Cardiology by : Alexander Sandor Nadas
Download or read book Pediatric Cardiology written by Alexander Sandor Nadas and published by W.B. Saunders Company. This book was released on 1972 with total page 776 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Pharmacology of Potassium Channels by : Nikita Gamper
Download or read book Pharmacology of Potassium Channels written by Nikita Gamper and published by Springer Nature. This book was released on 2021-09-27 with total page 546 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aim of the present book is to comprehensively review current advances in understanding of genetics, structural biology, pharmacology of potassium channels and their roles in disease as well as to identify current gaps in knowledge. The ultimate goal is to provide a scientific foundation for better understanding of modulatory mechanisms and pharmacology of potassium channels and to use this understanding to drive future drug discovery. This book will be a must-have for academic and industrial scientists interested in physiology, pharmacology, pathology and structure-functional relationships of ion channels. The book will also be helpful for lecturers and students in the college and university classrooms, as well as for anyone interested in the state-of-the art in modern cell biology, physiology and pharmacology.
Book Synopsis The hERG Cardiac Potassium Channel by : Derek J. Chadwick
Download or read book The hERG Cardiac Potassium Channel written by Derek J. Chadwick and published by John Wiley & Sons. This book was released on 2005-04-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book draws together contributions from basic, pharmaceutical and clinical sciences aimed at a better understanding of the structure and function of hERG and the molecular basis for compound binding. It features regulatory authority perspectives on preferred preclinical test systems and includes topics on hERG channel gating, regulation of functional expression, pharmacological properties of hERG/IKr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks. Better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias should ultimately lead to the development of important, new and safer medicines.
Book Synopsis Cardiac Potassium Channel Disorders, An Issue of Cardiac Electrophysiology Clinics by : Mohammad Shenasa
Download or read book Cardiac Potassium Channel Disorders, An Issue of Cardiac Electrophysiology Clinics written by Mohammad Shenasa and published by Elsevier Health Sciences. This book was released on 2016-06-10 with total page 265 pages. Available in PDF, EPUB and Kindle. Book excerpt: This issue of Cardiac Electrophysiology Clinics, edited by Drs. Mohammad Shenasa and Stanley Nattel, will review Cardiac Potassium Channel Disorders in depth. Topics covered include but are not limited to: Molecular Biology of Cardiac Potassium Channels; Genetic Control of Potassium Channels; Potassium Channel Remodeling in Heart Disease; Gender-specific Effects of Potassium Channel Blockers; Pharmacogenetics of Potassium Channel Blockers; Multichannel Blockers; Selective Potassium Channel Blockers; and Proarrhythmic and Torsadogenic Effects of Potassium Channel Blockers in Patients.
Book Synopsis CARDIAC POTASSIUM CHANNEL HERG IS REGULATED BY UBIQUITIN LIGASE NEDD4-2 by : HEIDI. SHALLOW
Download or read book CARDIAC POTASSIUM CHANNEL HERG IS REGULATED BY UBIQUITIN LIGASE NEDD4-2 written by HEIDI. SHALLOW and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Regulation of Cardiac Potassium Channels in Health and Disease by : Hannah Aizad Ledford
Download or read book Regulation of Cardiac Potassium Channels in Health and Disease written by Hannah Aizad Ledford and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Background: Cardiac potassium channels are implicated in a range of inherited and acquired ion channelopathies. Consequently, the regulation of potassium channels is a critical process; malfunction of which results in changes to membrane surface expression, current density, and channel kinetics. Decreases or increases in current can arise from defects in the channels themselves or from dysregulation by chaperone, trafficking, degradation, or accessory proteins, in addition to intracellular and extracellular factors (e.g. Ca2+ concentrations, second messenger signaling molecules, hormonal influences, ion concentrations, and pH). Here, we investigated the effects of regulatory mechanisms on potassium channel function and cardiac arrhythmogenesis. We evaluated the roles of interacting proteins on atrial and ventricular K+ channel function. Using heterologous expression systems (HEK 293 cells), mouse models, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we evaluated the impacts of quality control mechanisms on the human ether-à-go-go related gene (hERG) K+ channel; interacting proteins on small-conductance Ca2+-activated K+ channels (SK); and anion exchanger Slc26a6 on cardiac excitability and action potential. Specifically, we tested the hypotheses that E3 ubiquitin ligase, RNF207, regulates hERG channel expression and function through endoplasmic reticulum (ER)-associated degradation (chapter 2); calmodulin (CaM) mutants decrease SK2 current density through regulation of channel activation kinetics (chapter 3); [alpha]-actinin and filamin A regulate SK2 channel trafficking and surface expression (chapter 4); and Slc26a6 regulates cardiac excitability and action potential via its effects on intracellular pH and membrane potential (chapter 5). Methods and Results: To further evaluate these effects, we utilized a combination of electrophysiology, molecular biology, and imaging techniques. Whole-cell voltage-clamp, perforated patch action potential recordings, co-immunoprecipitation, degradation and ubiquitinylation assays, and immunofluorescence through confocal microscopy and stimulated emission depletion (STED) high-resolution microscopy were used in this study. We found that wild-type RNF207 is able to ubiquitinylate mutant hERG subunits (T613M; hERG[subscript T613M]), whereas mutant RNF207 (G603fs; RNF207[subscript G603fs]) fails to tag mutant hERG for degradation, allowing significant reduction in current density. SK2 channel surface expression was shown to be significantly enhanced by alpha-actinin and filamin a coexpression. SK2 current density was regulated by Ca2+-CaM activation, which was altered in the presence of CaM mutants. Lastly, we found that knockdown of Slc26a6 resulted in significantly prolonged action potential duration, decreased calcium transients, and intracellular pH irregularities. Conclusions Regulatory mechanisms play a key role in K+ channel expression and function. Potentially detrimental effects of heterozygously inherited channel mutations, which would otherwise be masked, may be revealed in the case of simultaneously inherited mutations in quality control mechanisms. Consequently, the effects of mutations in interacting proteins, cardiac ion channels or exchangers, and intracellular messengers may be widespread and warrants further study.
Book Synopsis Molecular Basis of Cardiovascular Disease by : Kenneth R. Chien
Download or read book Molecular Basis of Cardiovascular Disease written by Kenneth R. Chien and published by . This book was released on 2004 with total page 760 pages. Available in PDF, EPUB and Kindle. Book excerpt: The 2nd Edition of this heralded companion to Braunwald's Heart Disease explores the molecular mechanisms of cardiology and the scientific advances that are changing the practice of cardiology today. International experts discuss the role of genetics in cardiovascular disease the molecular basis of ischemic disease, thrombosis and hypertension genetic mapping approaches to inherited disorders biologically targeted agents for hypertension and heart failure and much more. Abundant figures and tables illustrate key concepts. Addresses most common cardiovascular problems from a molecular standpoint. Explores developing treatments for cardiovascular problems based on genetics. Provides references to Braunwald's Heart Disease, 6th Edition Examines today's cutting edge advances in molecular cardiology and the future of gene therapy, Examines the implications of cellular cholesterol metabolism in health and disease. . Delivers up-to-date information on understanding the origin of inherited disease.
Book Synopsis The Mechanism of Action of External Protons on HERG Potassium Channels by : Yu Shi
Download or read book The Mechanism of Action of External Protons on HERG Potassium Channels written by Yu Shi and published by . This book was released on 2018 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt: Myocardial ischemia occurs when there is a reduction of blood flow to the heart due to blockage of an artery, causing inefficient delivery of oxygen and nutrients to the heart muscle. Acidosis is one of the major consequences during myocardial ischemia and affects a wide array of ion channels in the heart that may predispose individuals to cardiac arrhythmia. The human ether-à-go-go (hERG) related gene encodes the potassium channel that conducts the IKr current, which is responsible for the repolarization phase of the cardiac action potential and is particularly sensitive to external acidosis. External acidosis had been well observed to reduce hERG channel overall conductance, right-shift the voltage-dependence of activation, and accelerate deactivation rate, all of which lead to a loss-of-function effect on the hERG channels. We hypothesized that this can prolong action potential duration, increase susceptibility of individuals to long QT syndrome and reduce the protective current against premature ectopic beat. My first study aimed to determine the site and mechanism for the right-shift in the voltage-dependence of activation. I found that external protons disrupt stable interactions formed by the cation binding pocket, compose of three acidic residues: D456, D460 in S2, and D509 in S3, with positive charges in S4 to destabilize the activated voltage sensor. My second study aims to determine the site and mechanism for the acceleration of deactivation induced by external protons. Using voltage-clamp fluorimetry and gating current measurement with long duration protocols to measure voltage sensor mode-shift, we determined that external protons reduced the voltage sensor mode-shift by right shifting the voltage-dependence of deactivation suggesting that the relaxed conformation of the voltage sensor is destabilized and that D509 is a critical protonation site. In my last study, I used zebrafish heart as a translational model, with the optical mapping technique to investigate the effect of external protons on the overall cardiac action potential. We discovered that at low pH, the cardiac action potential is significantly prolonged, triangulation is increased, and the electrical restitution curve is flattened, which are all predictors for arrhythmogenicity.
Book Synopsis Potassium Channels in Cardiovascular Biology by : Stephen L. Archer
Download or read book Potassium Channels in Cardiovascular Biology written by Stephen L. Archer and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 962 pages. Available in PDF, EPUB and Kindle. Book excerpt: Potassium channels (K+) are membrane-spanning proteins which serve many important functions and are becoming a hot topic in physiology. K+ channels determine or modulate many functions of vascular smooth muscle, endothelial and inflammatory cells, and thus are central to regulation of arterial tone and control of cell proliferation. They are also promising targets for antihypertensive treatments with drugs which open and close specific types of K+ channels, making for an active field of research. With their ability to control vascular tone, voltage-gated K+ channels play a significant role in both pulmonary and systemic hypertension as well as in cardiac arrhythmias. This book will highlight the latest discoveries by leading researchers pertaining to the role of K+ channels in the heart and blood vessels in normal physiology and a variety of disease states.
Book Synopsis Cardiac Repolarization by : Ihor Gussak
Download or read book Cardiac Repolarization written by Ihor Gussak and published by Springer Science & Business Media. This book was released on 2003-03-13 with total page 549 pages. Available in PDF, EPUB and Kindle. Book excerpt: A comprehensive review of all the latest developments in cardiac electrophysiology, focusing on both the clinical and experimental aspects of ventricular repolarization, including newly discovered clinical repolarization syndromes, electrocardiographic phenomena, and their correlation with the most recent advances in basic science. The authors illuminate the basic electrophysiologic, molecular, and pharmacologic mechanisms underlying ventricular repolarization, relate them to specific disease conditions, and examine the future of antiarrhythmic drug development based on both molecular and electrophysiological properties. They also fully review the clinical presentation and management of specific cardiac repolarization conditions.
Book Synopsis Acquired Long QT Syndrome by : A. John Camm
Download or read book Acquired Long QT Syndrome written by A. John Camm and published by John Wiley & Sons. This book was released on 2008-04-15 with total page 208 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent years there has been considerable interest in the diagnosis and understanding of ventricular repolarisation, particularly the QT interval prolongation and abnormal T and T/U wave morphology associated with torsades de pointes. Advances in ion channel cloning have greatly improved our understanding of the role of ionic channels in mediating cardiac repolarisation. Unfortunately, it is increasingly recognised that a number of drugs, both those associated with altering repolarisation, and others for non-cardiac conditions can increase the propensity for polymorphic ventricular tachycardia, syncope and even ventricular fibrillation and sudden death. In this volume, arrhythmia specialists from St. George’s Hospital Medical School, London discuss the mechanisms behind QT prolongation and torsades de pointes. They focus particularly on the risk of individual cardiac and non-cardiac drugs in provoking long QT syndrome, providing a comprehensive review which will be useful for all electrophysiologists treating polymorphic ventricular tachycardias, and will expose important regulatory issues for pharmaceutical authorities and for the wider medical community.
Book Synopsis Determining the Molecular Mechanism Modulating Interactions Between Cardiac Potassium Channel [alpha]-subunit Proteins HERG and KvLQT1 by : Yeon Joo Lee
Download or read book Determining the Molecular Mechanism Modulating Interactions Between Cardiac Potassium Channel [alpha]-subunit Proteins HERG and KvLQT1 written by Yeon Joo Lee and published by . This book was released on 2015 with total page 66 pages. Available in PDF, EPUB and Kindle. Book excerpt: KvLQT1 and hERG are the voltage-gated K+ channel [alpha]-subunits of the cardiac repolarizing currents IKs and IKr, respectively. These currents function to maintain proper action potential durations in cardiomyocytes to ultimately promote a normal heartbeat. Mutations in KCNQ1 or hERG can lead to a loss of proper function in these currents, resulting in arrhythmias. Previous research in transgenic model organisms demonstrated that interactions between pore mutants of KvLQT1 and hERG exist, resulting in mutual downregulation of their respective currents. In addition, direct protein-protein interactions between wild-type hERG and KvLQT1, and more specifically between the COOH-termini of the two proteins, have been established. These interactions have been shown to result in downregulation of the repolarizing currents in heterologous cells. We hypothesize that hERG-KvLQT1 interactions are abrogated through direct binding of cAMP to the cyclic nucleotide binding homology domain (CNBhD) in the C-terminus of hERG, rather than by downstream, PKA-mediated effects. In order to delineate the molecular mechanism underlying these interactions, quantitative FRET analyses were performed on human embryonic kidney (HEK) cells co-expressing either wild-type hERG and KvLQT1, or the V822M hERG mutant and wild-type KvLQT1. Intracellular cAMP levels were elevated through membrane-permeable cAMP analogs and IBMX. Mean FRET efficiency of wild-type hERG and KvLQT1 was significantly reduced in the presence of elevated intracellular cAMP levels, while the mean FRET efficiency of mutant hERG and KvLQT1 was not significantly affected. The effect of elevated cAMP levels on the interactions between wild-type hERG and KvLQT1 compared to those between mutant hERG and KvLQT1 still remains inconclusive. In light of current progress in the field, however, the potential for cAMP-dependent PKA phosphorylation of hERG and/or KvLQT1 will also be explored. This work potentially furthers our understanding of the physiological regulation of hERG-KvLQT1 interactions and its implications on cardiac arrhythmias in both healthy and diseased states, as well as characterizes novel interactions between two distinct potassium channel families.
Book Synopsis Anesthetic Pharmacology by : Alex S. Evers
Download or read book Anesthetic Pharmacology written by Alex S. Evers and published by Cambridge University Press. This book was released on 2011-03-10 with total page 2902 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.
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