Download or read book Trafficking of Cardiac Ion Channels written by Marcel Verges and published by MDPI. This book was released on 2021-04-27 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein sorting and trafficking are regulated by well-conserved mechanisms. These allow a distinctive set of resident proteins to be present in the correct subcellular organelle, which is required for proper cell functioning. Voltage-gated ion channels, as responsible for cardiomyocyte action potential, must be properly localized. They participate in cell excitability and electrical coupling, ensuring uninterrupted and rhythmic heart beating. Ion channel complexes comprise one or more pore-forming α subunits, associated β subunits, and additional proteins. Channel localization and function are regulated by the β subunits and associated proteins, such as cytoskeletal elements, cell-adhesion molecules, and adaptors. These influence protein targeting, anchoring, and retention in specific surface domains along the cardiomyocyte sarcolemma, such as intercalated discs, T-tubules, or the lateral membrane. Alterations in ion channel trafficking are the cause of channelopathies associated with inherited arrhythmias leading to sudden death. An outstanding question is how these molecular alterations lead to disease. In this volume, scientists share their vision to understand how cardiac ion channel trafficking is regulated and how it may become altered, leading to channelopathies that often turn into deadly arrhythmias. Data generated can be translated to a clinical context, hopefully turning into approaches to help prevention and treatment, which is of utmost importance, both medically and socially.
Download or read book Ion Channel Trafficking and Cardiac Arrhythmias written by Marcel A.G. van der Heyden and published by Frontiers Media SA. This book was released on 2018-12-06 with total page 123 pages. Available in PDF, EPUB and Kindle. Book excerpt: A well-adjusted expression of cardiac ion channels at the sarcolemma is of crucial importance for normal action potential formation and thus cardiac function. The cellular processes that transport channel proteins from the endoplasmic reticulum towards specified regions on the sarcolemmal membrane, and subsequently take them from the plasma membrane to the protein degradation machinery are commonly known as trafficking. The research field recognizes that aberrant channel trafficking stands at the basis of many congenital and acquired arrhythmias. The collection of papers in this eBook provides state-of-the-art insight into the world of ion channel trafficking research.
Download or read book Ion Channel Trafficking and Cardiac Arrhythmias written by and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: A well-adjusted expression of cardiac ion channels at the sarcolemma is of crucial importance for normal action potential formation and thus cardiac function. The cellular processes that transport channel proteins from the endoplasmic reticulum towards specified regions on the sarcolemmal membrane, and subsequently take them from the plasma membrane to the protein degradation machinery are commonly known as trafficking. The research field recognizes that aberrant channel trafficking stands at the basis of many congenital and acquired arrhythmias. The collection of papers in this eBook provides state-of-the-art insight into the world of ion channel trafficking research.
Download or read book Insights Into Assembly and Trafficking of the Cardiac Small conductance Calcium activated Potassium Channel SK2 written by Sassan Rafizadeh and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Proper mechanical activity of the heart is delicately interrelated with its timely electrical activation. It is the underlying ionic currents in each cell that lead to electrical activity, manifested as the cardiac action potential. In order to have a normal cardiac action potential, a specific number of functional ion channels need to be present on the plasma membrane. Defects in channel assembly or trafficking may lead to abnormalities in the corresponding ionic currents and shape of the action potential, which may lead to cardiac arrhythmias. The most prominent type of arrhythmia is atrial fibrillation (AF), which is associated with a significant increase in the risk of stroke. The incidence of AF is projected to increase three-fold by 2050 and therapeutic options for AF remain suboptimal. Current pharmacological therapies are associated with extracardiac toxicity while catheter ablation is invasive and can be associated with serious adverse events.Our group, as well as others, have previously documented the expression of several isoforms of small-conductance Ca2+ -activated K+ (SK) channels in human and mouse atrial myocytes. SK channels mediate the repolarization phase of the atrial action potential, with little effect on ventricular excitation. Indeed, we have previously documented that SK2 channel knock-out mice are prone to the development of AF. On the other hand, a recent study by Diness JG, et al. suggests that inhibition of Ca2+ activated K+ current may prevent AF. Taken together, these studies underpin the importance of these channels in atria and their potential to serve as a future therapeutic target for AF. Three isoforms of SK channel subunits (SK1, SK2 and SK3) are found to be expressed with SK2 as the most predominant isotype. In the first portion (CHAPTER 2) of this dissertation, I investigate the heteromultimeric formation and the domain necessary for the assembly of three SK channel subunits (SK1-SK3). My biochemical and functional data provides evidence for the formation of heteromultimeric complexes among different SK channel subunits in atrial myocytes. Using an innovative patch-clamp technique, applied here for the first time in cardiac myocytes, I show reduction of I[K,Ca] via inhibition of heteromultimerization. Since SK channels are predominantly expressed in atrial myocytes, specific ligands of the different isoforms of SK channel subunits may offer a unique therapeutic opportunity to directly modify atrial cells without interfering with ventricular myocytes. In addition to having proper subunit assembly and channel formation, there need to be a precise number of channels at specific locations on the plasma membrane. This means that there must be highly regulated sorting and trafficking pathways for ion channels. The importance of these processes is underscored by a number of disease conditions that involve mishandled trafficking of membrane proteins. It is important to note that the complete intracellular trafficking pathways are not known for any single channel. In the subsequent chapters, I identify [alpha]-actinin2 and Filamin A molecules, as important regulators of SK2 channel trafficking. Using various functional methods, including total internal reflection fluorescence microscopy (TIRF-M), I show SK2 channel interacts with FLNA to increase number of channels on the sarcolemma through increasing rate of recycling via recycling endosomes. I also show increased forward trafficking of SK2 as a result of interaction with [alpha]-actinin2 via an early endosomal-mediated trafficking pathway. Insight into the trafficking of SK2 channels may serve as a novel approach to modify SK2 current and atrial excitability without interfering with ventricular activity. The work done advances a new frontier towards understanding membrane localization of ion channels in cardiac muscle and other excitable cells. The demonstration of the mechanisms for targeting, anchoring and cell surface expression of the channel would help further understanding the ion channel function.
Download or read book Handbook of Ion Channels written by Jie Zheng and published by CRC Press. This book was released on 2015-02-25 with total page 691 pages. Available in PDF, EPUB and Kindle. Book excerpt: The New Benchmark for Understanding the Latest Developments of Ion Channels Ion channels control the electrical properties of neurons and cardiac cells, mediate the detection and response to sensory stimuli, and regulate the response to physical stimuli. They can often interact with the cellular environment due to their location at the surface of cells. In nonexcitable tissues, they also help regulate basic salt balance critical for homeostasis. All of these features make ion channels important targets for pharmaceuticals. Handbook of Ion Channels illustrates the fundamental importance of these membrane proteins to human health and disease. Renowned researchers from around the world introduce the technical aspects of ion channel research, provide a modern guide to the properties of major ion channels, and present powerful methods for modeling ion channel diseases and performing clinical trials for ion channel drugs. Conveniently divided into five parts, the handbook first describes the basic concepts of permeation and gating mechanisms, balancing classic theories and the latest developments. The second part covers the principles and practical issues of both traditional and new ion channel techniques and their applications to channel research. The third part organizes the material to follow the superfamilies of ion channels. This part focuses on the classification, properties, gating mechanisms, function, and pharmacology of established and novel channel types. The fourth part addresses ion channel regulation as well as trafficking and distribution. The final part examines several ion channel-related diseases, discussing genetics, mechanisms, and pharmaceutical advances.
Download or read book Voltage Gated Sodium Channels written by Peter C. Ruben and published by Springer Science & Business Media. This book was released on 2014-04-15 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt: A number of techniques to study ion channels have been developed since the electrical basis of excitability was first discovered. Ion channel biophysicists have at their disposal a rich and ever-growing array of instruments and reagents to explore the biophysical and structural basis of sodium channel behavior. Armed with these tools, researchers have made increasingly dramatic discoveries about sodium channels, culminating most recently in crystal structures of voltage-gated sodium channels from bacteria. These structures, along with those from other channels, give unprecedented insight into the structural basis of sodium channel function. This volume of the Handbook of Experimental Pharmacology will explore sodium channels from the perspectives of their biophysical behavior, their structure, the drugs and toxins with which they are known to interact, acquired and inherited diseases that affect sodium channels and the techniques with which their biophysical and structural properties are studied.
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.
Download or read book The Cytoskeleton written by James Spudich and published by . This book was released on 1996 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Voltage gated Sodium Channels Structure Function and Channelopathies written by Mohamed Chahine and published by Springer. This book was released on 2018-06-04 with total page 450 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a timely state-of-the-art overview of voltage-gated sodium channels, their structure-function, their pharmacology and related diseases. Among the topics discussed are the structural basis of Na+ channel function, methodological advances in the study of Na+ channels, their pathophysiology and drugs and toxins interactions with these channels and their associated channelopathies.
Download or read book Ion Channels Channel Chemical Biology Engineering and Physiological Function written by and published by Academic Press. This book was released on 2021-06-12 with total page 454 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion Channels, Part C, Volume 653 in the Methods in Enzymology series, highlights new advances in the field with this new volume presenting interesting chapters on a variety of topics, including Nonsense suppression in ion channels, Engineering Ion Channels Using Protein Trans-splicing, Probing Ion Channel Neighborhoods Using APEX, STX based probes for NaVs, ANAP: a versatile, fluorescent probe of ion channel gating and regulation, High Throughput Screens for Small Molecule Ion Channel Modulators, Using toxins to study ion channels, Re/de-constructing ubiquitin regulation of ion channels, Tethered Peptide Toxins for Ion Channels, Voltage-Sensing Phosphatase Molecular Engineering, and more. Additional chapters cover Engineering excitable cells, Stretch and Poke Stimulation of Mechanically-Activated Ion Channels, Optical Control of STIM Channels, High Throughput Electrophysiological Evaluation of Mutant Ion Channels, Evaluating BEST1 Mutations in RPE Stem Cells, Long Read Transcript Profiling of Ion Channel Splice Variants, Permeation of Connexin Channels, Ratiometric pH indicator for melanosomes and lysosomes, and Ion channels in the epithelial cells of the choroid plexus. Provides the authority and expertise of leading contributors from an international board of authors Presents the latest release in the Methods in Enzymology series
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.
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.
Download or read book Ion Channel Diseases written by and published by Academic Press. This book was released on 2011-09-06 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion channel dysfunction in humans leads to impairment of the excitable processes necessary for the normal function of several tissues, such as muscle and brain. It follows that an increasing number of human diseases have been associated with malfunctioning ion channels, many of which have a genetic component. This volume of Advances in Genetics presents a broad and comprehensive overview of the inherited channelopathies in humans, including clinical, genetic and molecular aspects of these conditions. Keeping true to the scope of the serial, novel genomic and modeling research approaches and a review of potential therapeutic approaches for each of these conditions are also incorporated.
Download or read book Structure Function and Modulation of Neuronal Voltage Gated Ion Channels written by Valentin K. Gribkoff and published by John Wiley & Sons. This book was released on 2008-12-09 with total page 505 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book discusses voltage-gated ion channels and their importance in drug discovery and development. The book includes reviews of the channel genome, the physiological bases of targeting ion channels in disease, the unique technologies developed for ion channel drug discovery, and the increasingly important role of ion channel screening in cardiac risk assessment. It provides an important reference for research scientists and drug discovery companies.
Download or read book Store Operated Calcium Channels written by and published by Academic Press. This book was released on 2013-07-24 with total page 307 pages. Available in PDF, EPUB and Kindle. Book excerpt: Store-operated calcium channels are found in most animal cells and regulate many cellular functions including cell division, growth, differentiation, and cell death. This volume provides a concise and informative overview of the principles of store-operated calcium entry and the key developments in the field from researchers who have led these advances. The overall goal of the volume is to provide interested students and investigators with sufficient information to enable a broad understanding of the progress and current excitement in the field. The volume contains a wealth of information that even experienced investigators in the field will find useful. The volume provides a comprehensive overview of the mechanisms and functions of store-operated calcium channels Contributors are authoritative researchers who have produced important advances in the field The volume is well-illustrated with cartoons and data to facilitate easy comprehension of the subject
Download or read book Ion Channels in Health and Disease written by Geoffrey S. Pitt and published by Academic Press. This book was released on 2016-07-11 with total page 394 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion Channels in Health and Disease provides key insight to allow researchers to generate discoveries across disease states. A single resource that integrates disparate areas of biology and disease ion channel biology, this publication includes cross-referencing for disease, channels, and tissues. Offers a broad view of research of interest to early and experienced researchers across biological and biomedical research. Provides an overview of fundamental concepts in ion channels research to link defects in human disease Written in an accessible manner, without jargon Provides a helpful, easy cross-reference for diseases, channels, and tissues
Download or read book Cholesterol Binding and Cholesterol Transport Proteins written by J. Robin Harris and published by Springer Science & Business Media. This book was released on 2010-03-10 with total page 641 pages. Available in PDF, EPUB and Kindle. Book excerpt: Knowledge of cholesterol and its interaction with protein molecules is of fundamental importance in both animal and human biology. This book contains 22 chapters, dealing in depth with structural and functional aspects of the currently known and extremely diverse unrelated families of cholesterol-binding and cholesterol transport proteins. By drawing together this range of topics the Editor has attempted to correlate this broad field of study for the first time. Technical aspects are given considerable emphasis, particularly in relation cholesterol reporter molecules and to the isolation and study of membrane cholesterol- and sphingomyelin-rich "raft" domains. Cell biological, biochemical and clinical topics are included in this book, which serve to emphasize the acknowledged and important benefits to be gained from the study of cholesterol and cholesterol-binding proteins within the biomedical sciences and the involvement of cholesterol in several clinical disorders. It is hoped that by presenting this topic in this integrated manner that an appreciation of the fact that there is much more that needs to be taken into account, studied and understood than the widely discussed "bad and good cholesterol" associated, respectively, with the low- and high-density lipoproteins, LDL and HDL.
