CaMKII Phosphorylation of the Voltage-gated Sodium Channel Nav1.6 Regulates Channel Function and Neuronal Excitability PDF Download
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Author: Agnes Sara Zybura
Publisher:
ISBN:
Category :
Languages : en
Pages : 622
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Book Description
Voltage-gated sodium channels (Navs) undergo remarkably complex modes of modulation to fine tune membrane excitability and neuronal firing properties. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Thus, Nav1.6 modulation and dysfunction may profoundly impact the input-output properties of neurons in normal and pathological conditions. Phosphorylation is a powerful and reversible mechanism that exquisitely modulates ion channels. To this end, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) can transduce neuronal activity through phosphorylation of diverse substrates to serve as a master regulator of neuronal function. Because Nav1.6 and CaMKII are independently linked to excitability disorders, I sought to investigate modulation of Nav1.6 function by CaMKII signaling to reveal an important mechanism underlying neuronal excitability. Multiple biochemical approaches show Nav1.6 is a novel substrate for CaMKII and reveal multi-site phosphorylation within the L1 domain; a hotspot for post-translational regulation in other Nav isoforms. Consistent with these findings, pharmacological inhibition of CaMKII reduces transient and persistent sodium currents in Purkinje neurons. Because Nav1.6 is the predominant sodium current observed in Purkinje neurons, these data suggest that Nav1.6 may be modulated through CaMKII signaling. In support of this, my studies demonstrate that CaMKII inhibition significantly attenuates Nav1.6 transient and persistent sodium currents and shifts the voltage-dependence of activation to more depolarizing potentials in heterologous cells. Interestingly, I show that these functional effects are likely mediated by CaMKII phosphorylation of Nav1.6 at S561 and T642, and that each phosphorylation site regulates distinct biophysical characteristics of the channel. These findings are further extended to investigate CaMKII modulation of disease-linked mutant Nav1.6 channels. I show that different Nav1.6 mutants display distinct responses to CaMKII modulation and reveal that acute CaMKII inhibition attenuates gain-of-function effects produced by mutant channels. Importantly, computational simulations modeling the effects of CaMKII inhibition on WT and mutant Nav1.6 channels demonstrate dramatic reductions in neuronal excitability in Purkinje and cortical pyramidal cell models. Together, these findings suggest that CaMKII modulation of Nav1.6 may be a powerful mechanism to regulate physiological and pathological neuronal excitability.
Author: Agnes Sara Zybura
Publisher:
ISBN:
Category :
Languages : en
Pages : 622
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Book Description
Voltage-gated sodium channels (Navs) undergo remarkably complex modes of modulation to fine tune membrane excitability and neuronal firing properties. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Thus, Nav1.6 modulation and dysfunction may profoundly impact the input-output properties of neurons in normal and pathological conditions. Phosphorylation is a powerful and reversible mechanism that exquisitely modulates ion channels. To this end, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) can transduce neuronal activity through phosphorylation of diverse substrates to serve as a master regulator of neuronal function. Because Nav1.6 and CaMKII are independently linked to excitability disorders, I sought to investigate modulation of Nav1.6 function by CaMKII signaling to reveal an important mechanism underlying neuronal excitability. Multiple biochemical approaches show Nav1.6 is a novel substrate for CaMKII and reveal multi-site phosphorylation within the L1 domain; a hotspot for post-translational regulation in other Nav isoforms. Consistent with these findings, pharmacological inhibition of CaMKII reduces transient and persistent sodium currents in Purkinje neurons. Because Nav1.6 is the predominant sodium current observed in Purkinje neurons, these data suggest that Nav1.6 may be modulated through CaMKII signaling. In support of this, my studies demonstrate that CaMKII inhibition significantly attenuates Nav1.6 transient and persistent sodium currents and shifts the voltage-dependence of activation to more depolarizing potentials in heterologous cells. Interestingly, I show that these functional effects are likely mediated by CaMKII phosphorylation of Nav1.6 at S561 and T642, and that each phosphorylation site regulates distinct biophysical characteristics of the channel. These findings are further extended to investigate CaMKII modulation of disease-linked mutant Nav1.6 channels. I show that different Nav1.6 mutants display distinct responses to CaMKII modulation and reveal that acute CaMKII inhibition attenuates gain-of-function effects produced by mutant channels. Importantly, computational simulations modeling the effects of CaMKII inhibition on WT and mutant Nav1.6 channels demonstrate dramatic reductions in neuronal excitability in Purkinje and cortical pyramidal cell models. Together, these findings suggest that CaMKII modulation of Nav1.6 may be a powerful mechanism to regulate physiological and pathological neuronal excitability.
Author: Peter C. Ruben
Publisher: Springer Science & Business Media
ISBN: 3642415881
Category : Medical
Languages : en
Pages : 328
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Book Description
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.
Author: Dhrubajyoti Chowdhury
Publisher: Frontiers Media SA
ISBN: 2832509444
Category : Science
Languages : en
Pages : 206
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Book Description
Author: Douglas P. Zipes
Publisher: Elsevier Health Sciences
ISBN: 0323448887
Category : Medical
Languages : en
Pages : 1429
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Book Description
Rapid advancements in cardiac electrophysiology require today’s health care scientists and practitioners to stay up to date with new information both at the bench and at the bedside. The fully revised 7th Edition of Cardiac Electrophysiology: From Cell to Bedside, by Drs. Douglas Zipes, Jose Jalife, and William Stevenson, provides the comprehensive, multidisciplinary coverage you need, including the underlying basic science and the latest clinical advances in the field. An attractive full-color design features color photos, tables, flow charts, ECGs, and more. All chapters have been significantly revised and updated by global leaders in the field, including 19 new chapters covering both basic and clinical topics. New topics include advances in basic science as well as recent clinical technology, such as leadless pacemakers; catheter ablation as a new class I recommendation for atrial fibrillation after failed medical therapy; current cardiac drugs and techniques; and a new video library covering topics that range from basic mapping (for the researcher) to clinical use (implantations). Each chapter is packed with the latest information necessary for optimal basic research as well as patient care, and additional figures, tables, and videos are readily available online. New editor William G. Stevenson, highly regarded in the EP community, brings a fresh perspective to this award-winning text. Expert Consult eBook version included with purchase. This enhanced eBook experience allows you to search all of the text, figures, images, videos (including video updates), glossary, and references from the book on a variety of devices.
Author: Douglas P. Zipes
Publisher: Elsevier Health Sciences
ISBN: 145572856X
Category : Medical
Languages : en
Pages : 1395
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Book Description
Cardiac Electrophysiology: From Cell to Bedside puts the latest knowledge in this subspecialty at your fingertips, giving you a well-rounded, expert grasp of every cardiac electrophysiology issue that affects your patient management. Drs. Zipes, Jalife, and a host of other world leaders in cardiac electrophysiology use a comprehensive, multidisciplinary approach to guide you through all of the most recent cardiac drugs, techniques, and technologies. Get well-rounded, expert views of every cardiac electrophysiology issue that affects your patient management from preeminent authorities in cardiology, physiology, pharmacology, pediatrics, biophysics, pathology, cardiothoracic surgery, and biomedical engineering from around the world. Visually grasp and easily absorb complex concepts through an attractive full-color design featuring color photos, tables, flow charts, ECGs, and more! Integrate the latest scientific understanding of arrhythmias with the newest clinical applications, to select the right treatment and management options for each patient. Stay current on the latest advancements and developments with sweeping updates and 52 NEW chapters - written by many new authors - on some of the hottest cardiology topics, such as new technologies for the study of the molecular structure of ion channels, molecular genetics, and the development of new imaging, mapping and ablation techniques. Get expert advice from Dr. Douglas P. Zipes - a leading authority in electrophysiology and editor of Braunwald's Heart Disease and the Heart Rhythm Journal - and Dr. Jose Jalife - a world-renowned leader and researcher in basic and translational cardiac electrophysiology. Access the full text online at Expert Consult, including supplemental text, figures, tables, and video clips. Your purchase entitles you to access the web site until the next edition is published, or until the current edition is no longer offered for sale by Elsevier, whichever occurs first. If the next edition is published less than one year after your purchase, you will be entitled to online access for one year from your date of purchase. Elsevier reserves the right to offer a suitable replacement product (such as a downloadable or CD-ROM-based electronic version) should online access to the web site be discontinued.
Author: Maren Engelhardt
Publisher: Frontiers Media SA
ISBN: 2889194884
Category :
Languages : en
Pages : 234
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Book Description
Ever since Santiago Ramón y Cajal sketched his captivating panels of the microscopic structure of the brain with its vast diversity of neuronal morphology over a century ago, scientists have been drawn to this seemingly chaotic network of neurites and processes to uncover how structure relates to function. During the course of a century, we have moved from merely describing neuronal and glial morphology to furthering our understanding of such intricate processes as organelle and factor transport, cellular compartmentalization, neuronal polarity, cytoskeleton dynamics, neurite pathfinding, and the impact of pathophysiological insult on these structures and events. Yet to this day, and likely for the foreseeable future, much work remains to be done to fully grasp the exceptional role of neurites for the function of larger neuronal ensembles and networks. While the somatodendritic domain of neurons has been in the focus of attention for many years, mostly because of its great dynamic remodeling capacity during events of plasticity (e.g. learning), the axonal domain has somehow remained in the background despite the fact that especially recent comprehensive studies from various fields of research underline the axon’s contribution to dynamic plasticity processes. Consequently, this Research Topic focuses on the many exciting aspects of axonal neurobiology – ranging from membrane composition and molecular determination during development to axonal domain specialization and physiology in health and disease. In Chapter 1 “Axons in the PNS”, Bombeiro et al. use immunodeficient mice to study the role of lymphocytes during the regeneration of peripheral nerves, showing that the modulation of immune responses after injury can be an efficient approach to enhance nerve regeneration in the PNS. Using a DRG model, Berbusse et al. identify the onset of damage to mitochondrial structure and dynamics as a key event during early axon degeneration and provide evidence that Nmnat1, a member of the family of nicotinamide-nucleotide adenylyltransferases, can have protective effects by preserving normal mitochondrial integrity and dynamics. In another study of PNS nerve regeneration, Law et al. use proteomics approaches via Mass Spectrometry to provide evidence that rosovitine, a synthetic purine nucleoside analog, can successfully promote PNS axon regeneration. In Chapter 2 “Axonal development in the central nervous system”, Yoshimura et al. analyze specialized axonal domains, namely the axon initial segment and nodes of Ranvier, with regards to their expression profiles of the major scaffolding protein ßIV-spectrin. Super resolution microscopy reveals a potential developmental switch of spectrin isoforms at both axonal domains. In a related study, also using super resolution microscopy, Leterrier et al. examine a potential reciprocal role of membrane partners in ankyrin-G targeting and stabilization at the axonal membrane during development. The authors demonstrate a tight and precocious association of ankyrin-G with its membrane partners. Höfflin et al. address the question of axon initial segment morphology across different cell classes in cortical organotypic slice cultures and find a surprising heterogeneity especially between pyramidal cells and interneurons in primary visual cortex. In a major step towards establishing a successful live label of the axon initial segment, Dumitrescu et al. report the development of a genetically-encoded construct consisting of a voltage-gated sodium channel intracellular domain fused to yellow fluorescent protein (YFP-NaVII-III). Nelson and Jenkins then provide a comprehensive Review article on the axon initial segment and nodes of Ranvier with a special focus on the various scaffolding protein isoforms and their role in human disease. In Chapter 3 “Axonal physiology and plasticity”, Nikitin et al. investigate fast onset dynamics of action potentials during neuronal development in vitro, showing that encoding of high frequencies improves upon culture maturation, accompanied by the development of passive electrophysiological properties and action potential generation. Using pharmacological and RNA interference approaches, Tapia et al. provide evidence that cannabinoid receptors and their ligands can modulate dendritic morphology and thus, indirectly, also affect ankyrin-G accumulation at the axon initial segment. A Mini Review by Zbili et al. discusses the potential impact of subthreshold changes in presynaptic membrane potential before action potential initiation on neurotransmitter release, and which significant impact such mechanisms could have on information processing in neuronal circuits. Yamada and Kuba close this chapter with a Mini Review on axon initial segment plasticity with a particular focus on ion channels and the biophysics of excitability. In Chapter 4 “Axon degeneration and regeneration”, Hamada et al. investigate the often overlooked question to which extent myelin loss affects action potential propagation along distal branch points and axon collaterals. Using the cuprizone demyelination model and optical voltage-sensitive dye imaging, the authors uncover functional consequences of demyelination that reach well beyond the main axon. In a model of mild traumatic brain injury, Vascak et al. demonstrate complex aspects of this injury type on neocortical circuit function, including changes in inhibitory perisomatic input and axon initial segment-driven output in affected layer V neurons. In a Mini Review, Grosch et al. discuss recent advances in the field of Parkinson’s disease with a focus on early degeneration in dopaminergic and serotonergic neurons of the basal ganglia. The last two articles cover the topic of axonal regeneration. Li et al. investigate the role of activated astrocytes in spinal cord lesion and how their functional downregulation via an inhibitor of mitochondrial fission, Mdivi-1, could potentially have positive impact on lesion scar formation and axonal regeneration. In a final Review, Liu et al. highlight recent advances in the development of biomaterial scaffolds and cell transplantation strategies to combine two promising therapeutic approaches for spinal cord injury.
Author: Stefan I. McDonough
Publisher: Springer Science & Business Media
ISBN: 9780306478789
Category : Medical
Languages : en
Pages : 440
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Book Description
This volume reviews the current ability, future prospects, and physiological and medical significance of being able to distinguish pharmacologically among different calcium channel subtypes. Chapters are organized around broad concepts addressing the state of the field that naturally cover the pharmacology of each different calcium channel. Mechanistic information on drug-channel interactions is also presented in several chapters, as a theoretical and practical guide to working with calcium channel blockers in general.
Author: Ihor Gussak
Publisher: Springer Science & Business Media
ISBN: 1592593623
Category : Medical
Languages : en
Pages : 549
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Book Description
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.
Author: Donald W. Pfaff
Publisher: Springer
ISBN: 9781493934737
Category : Medical
Languages : en
Pages : 0
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Book Description
Edited and authored by a wealth of international experts in neuroscience and related disciplines, this key new resource aims to offer medical students and graduate researchers around the world a comprehensive introduction and overview of modern neuroscience. Neuroscience research is certain to prove a vital element in combating mental illness in its various incarnations, a strategic battleground in the future of medicine, as the prevalence of mental disorders is becoming better understood each year. Hundreds of millions of people worldwide are affected by mental, behavioral, neurological and substance use disorders. The World Health Organization estimated in 2002 that 154 million people globally suffer from depression and 25 million people from schizophrenia; 91 million people are affected by alcohol use disorders and 15 million by drug use disorders. A more recent WHO report shows that 50 million people suffer from epilepsy and 24 million from Alzheimer’s and other dementias. Because neuroscience takes the etiology of disease—the complex interplay between biological, psychological, and sociocultural factors—as its object of inquiry, it is increasingly valuable in understanding an array of medical conditions. A recent report by the United States’ Surgeon General cites several such diseases: schizophrenia, bipolar disorder, early-onset depression, autism, attention deficit/ hyperactivity disorder, anorexia nervosa, and panic disorder, among many others. Not only is this volume a boon to those wishing to understand the future of neuroscience, it also aims to encourage the initiation of neuroscience programs in developing countries, featuring as it does an appendix full of advice on how to develop such programs. With broad coverage of both basic science and clinical issues, comprising around 150 chapters from a diversity of international authors and including complementary video components, Neuroscience in the 21st Century in its second edition serves as a comprehensive resource to students and researchers alike.
Author: Mohamed Chahine
Publisher: Springer
ISBN: 3319902849
Category : Medical
Languages : en
Pages : 448
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Book Description
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.
