Novel Structural And Physiological Functions Of High Conductance K Channels Of The Slo Family

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Novel Structural And Physiological Functions Of High Conductance K Channels Of The Slo Family

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Author : Gonzalo Budelli
language : en
Publisher:
Release Date : 2013

Novel Structural And Physiological Functions Of High Conductance K Channels Of The Slo Family written by Gonzalo Budelli and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013 with Electronic dissertations categories.

The SLO family channels are high conductance K+ channels that are gated both by voltage and intracellular ions. Structurally they resemble voltage gated channels but have additional large conserved intracellular domains appended on the C-terminal that allow them to be gated by different intracellular ions. Two members of this unique family of K+ channels are Slo1 (BK) which is activated by Ca2+, and Slo2.2 (Slack) which is activated by sodium. Both channels are widely expressed in the brain and other tissues in many species from C. elegans to humans. The large conductance Ca2+- activated K+ channel (Slo1 or BK for Big conductance K+ channel) is widely distributed and controls many different physiological processes including cellular excitability, neurotransmitter release, muscle contraction, hair cell function, insulin release, and blood pressure. Defects in Slo1 channels have been associated with hypertension, autism and mental retardation, obesity, asthma, epilepsy, and cerebellar ataxia. Slo1 channels are activated by Ca2+, voltage, and Mg2+ through different allosteric pathways providing a model system to study allosteric coupling and pathways in channel gating and protein function. The structure of Slo1 has two functional domains, a "Core" consisting of seven transmembrane elements (S0-S6) which assemble to form a voltage sensing domain which allosterically confers voltage sensitivity to the pore gate domain, and a "Tail" that forms a large intracellular gating ring thought to confer Ca2+ and Mg2+ sensitivity through different transduction pathways from gating ring to Core. The large modular Slo1 channel is known to undergo many complex allosteric interactions during channel gating, some within subdomains of the Core itself, some within the massive Tail, and some between Tail and Core. Because of its great size and complexity it has not been possible to understand all these allosteric structural changes nor dissect the contributions of the different transduction pathways to channel gating. A new and valuable tool for answering these questions would be the ability to express the voltage-sensitive Core alone, free of the influence of the large and complex Tail. This would allow the determination of the baseline gating properties of the isolated Core, which would permit experiments such as adding the transduction pathways back one at a time and in combination, to reveal the functions of each. Unfortunately, it has not previously been possible to express the Core without the gating ring. However, we have been able to develop novel constructs of the Core without the gating ring that I have been able to express and analyze using the Xenopus oocyte heterologous expression system. I will show that currents from these constructs are from heterologously expressed gating ring-less channels and not from possible endogenously expressed channels. This allows determination for the first time, of the baseline properties of the Slo1 Core without passive or active allosteric input from the gating ring. The studies I performed show that the baseline properties of the isolated Core differ considerably from the properties of the intact Slo1 channel in the isolation of Ca2+. This shows that the gating ring imparts passive properties and interactions with the core, even in the absence of Ca2+. Thus, removing the gating ring reduces single-channel conductance ~30%, removes all Ca2+- and Mg2+-sensitivity, greatly reduces single channel mean open channel duration and burst duration; and right-shifts the G/V relation. Knowing these baseline properties of the Core then provides us with a novel tool and a guide for understanding the allosteric basis for gating in Slo1 channels. Such knowledge may facilitate the development of agents to restore normal function in genetic syndromes where Slo1 channels are involved. Also, this more complete understanding of how these complicated channels function could be important for understanding other channels that are activated by more than one factor (as TRP channels) or for other proteins which undergo complicated allosteric structural changes. The goal of the second project was to reveal the physiological relevance of Slo2 (Slack and Slick) Na+-dependent K+ channels. The discovery of high conductance Na+-dependent K+ channels in heart and brain presented a conundrum, the sodium concentrations needed to activate these channels in inside-out patches far exceeded the intracellular concentration of Na+ under normal physiological conditions. Thus, it was proposed that Na+-dependent K+ channels were an emergency conductance only activated under very special conditions such as during hypoxia or ischemia where the Na+ levels increase inside the cell. However, other reports indicated that these channels could be active under normal physiological conditions. Also, there is evidence of these channels being widely expressed all over the mammalian brain. I present data here showing that one of the largest components of the delayed outward current that is active under physiological conditions in many mammalian neurons, such as medium spiny neurons of the striatum and tufted-mitral cells of the olfactory bulb, is expressed by Na+-activated K+ channels and has previously gone unnoticed. Previous studies of K+ currents in mammalian neurons may have overlooked this large outward component because the sodium channel blocker tetrodotoxin (TTX) is typically used in studies of K+ channels. However, we found that TTX also eliminated this Na+-dependent delayed outward component in rat neurons as a secondary consequence. Unexpectedly, we found that the activity of persistent inward sodium current is highly effective at activating this large Na+-dependent (TTX sensitive) delayed outward current. Using siRNA techniques, I identified the Slo2.2 channel as a carrier of this delayed outward current. These findings have far reaching implications for many aspects of cellular and systems neuroscience, as well as clinical neurology and pharmacology. The final part of this dissertation involves the study of the effect of divalent cations on Slo2.2 channels. The activating effect of virtually all divalent cations on Slo1 is well documented, but the effect of divalent cations on Slo2.2 channels is largely unstudied. In exploring this question, I was surprised to observe that all of the divalent ions that activate Slo1 channels have the opposite effect on Slo2.2 channels; they reduce channel activity. After making this observation I turned my attention towards understanding the mechanism of blocking. I considered two hypotheses: 1) Divalent ions blocked the pore of Slo2.2 channels, and 2) Divalent ions functioned at a site away from the pore and either competed with sodium ion binding or produced allosteric changes leading to channel inhibition. My results indicate that the effect of divalent ions on Slo2.2 is not by blocking the pore. I also showed that the blocking effect of divalent cations on Slo2.2 channels is conserved in the orthologous channel from Drosophila which has been cloned in our lab. In addition, I show that the Drosophila Slo2 channel is sodium dependent, unlike the Slo2 channel in another invertebrate, C. elegans, which lacks sodium sensitivity and is instead, activated by Ca2+. Finally, by site-directed mutagenesis, we have tentatively located the site of interaction of divalent cations with the Slo2.2 channel. In the conclusion to this section, I discuss the possible physiological relevance of my findings to a proposed mechanism of action of Slo2 channels.

Medical Physiology 2e Updated Edition E Book

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Author : Walter F. Boron
language : en
Publisher: Elsevier Health Sciences
Release Date : 2012-01-13

Medical Physiology 2e Updated Edition E Book written by Walter F. Boron and has been published by Elsevier Health Sciences this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-01-13 with Medical categories.

Medical Physiology, in its updated 2nd edition, firmly relates molecular and cellular biology to the study of human physiology and disease. Drs. Walter Boron and Emile Boulpaep and a team of leading physiologists present you with practical, accurate coverage, continually emphasizing the clinical implications of the material. Each chapter explains the principles and organization of each body system, while more than 1400 high-quality, full-color line drawings and prominently featured clinical examples clarify every concept. This exceptionally detailed and comprehensive guide to physiology is ideal for a rich, straightforward, state-of-the-art understanding of this essential subject. Quickly review important content using prominent boxes included throughout the text to provide clinical examples of disordered physiology. Master difficult concepts with the use of 800 color drawings that feature balloon captions explaining key processes. Find information easily with the intuitive organization by body system and consistent style. Get up-to-date coverage of physiology with updated text and figures. Access the fully searchable text online at www.StudentConsult.com, along with Webnotes, Image Bank, 150 Self-assessment questions, and 10 physiology animations. Stay current thanks to updated material, including a new chapter on Physiology of Aging and a new section on hemostasis. Gain a clear visual understanding with a revised and updated art program of high-quality, full color line drawings and prominently featured clinical examples.

Big On Bk

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Author :
language : en
Publisher: Academic Press
Release Date : 2016-05-26

Big On Bk written by and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016-05-26 with Science categories.

Big on Bk: Current Insights into the Function of Large Conductance Voltage- and Ca2+- Activated K+ Channels at the Molecular, Cellular and Systemic Levels, a volume in the International Review of Neurobiology series, is a comprehensive overview of the state-of-the-art research into this area. It reviews current knowledge and understanding, and also provides a starting point for researchers and practitioners entering the field. The latest volume in the International Review of Neurobiology series Provides a broad coverage of subject matter at the molecular, cellular and systemic levels Presents an ideal resource for researchers and practitioners, and those just entering the field

Medical Physiology E Book

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Author : Walter F. Boron
language : en
Publisher: Elsevier Health Sciences
Release Date : 2016-03-29

Medical Physiology E Book written by Walter F. Boron and has been published by Elsevier Health Sciences this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016-03-29 with Medical categories.

For a comprehensive understanding of human physiology — from molecules to systems —turn to the latest edition of Medical Physiology. This updated textbook is known for its unparalleled depth of information, equipping students with a solid foundation for a future in medicine and healthcare, and providing clinical and research professionals with a reliable go-to reference. Complex concepts are presented in a clear, concise, and logically organized format to further facilitate understanding and retention. Clear, didactic illustrations visually present processes in a clear, concise manner that is easy to understand. Intuitive organization and consistent writing style facilitates navigation and comprehension. Takes a strong molecular and cellular approach that relates these concepts to human physiology and disease. An increased number of clinical correlations provides a better understanding of the practical applications of physiology in medicine. Highlights new breakthroughs in molecular and cellular processes, such as the role of epigenetics, necroptosis, and ion channels in physiologic processes, to give insights into human development, growth, and disease. Several new authors offer fresh perspectives in many key sections of the text, and meticulous editing makes this multi-authored resource read with one unified voice. Includes electronic access to 10 animations and copious companion notes prepared by the Editors.

Cell Physiology Source Book

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Author : Nicholas Sperelakis
language : en
Publisher: Gulf Professional Publishing
Release Date : 2001-08-02

Cell Physiology Source Book written by Nicholas Sperelakis and has been published by Gulf Professional Publishing this book supported file pdf, txt, epub, kindle and other format this book has been release on 2001-08-02 with Medical categories.

This authoritative book gathers together a broad range of ideas and topics that define the field. It provides clear, concise, and comprehensive coverage of all aspects of cellular physiology from fundamental concepts to more advanced topics. The Third Edition contains substantial new material. Most chapters have been thoroughly reworked. The book includes chapters on important topics such as sensory transduction, the physiology of protozoa and bacteria, the regulation of cell division, and programmed cell death. Completely revised and updated - includes 8 new chapters on such topics as membrane structure, intracellular chloride regulation, transport, sensory receptors, pressure, and olfactory/taste receptors Includes broad coverage of both animal and plant cells Appendixes review basics of the propagation of action potentials, electricity, and cable properties Authored by leading experts in the field Clear, concise, comprehensive coverage of all aspects of cellular physiology from fundamental concepts to more advanced topics

Regulatory Mechanisms Of Ca2 Activated Ion Channels And Their Impacts On Physiological Pathophysiological Functions

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Author : Yoshiaki Suzuki
language : en
Publisher: Frontiers Media SA
Release Date : 2022-04-27

Regulatory Mechanisms Of Ca2 Activated Ion Channels And Their Impacts On Physiological Pathophysiological Functions written by Yoshiaki Suzuki and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-04-27 with Science categories.

Potassium Channels In Cardiovascular Biology

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Author : Stephen L. Archer
language : en
Publisher: Springer Science & Business Media
Release Date : 2012-12-06

Potassium Channels In Cardiovascular Biology written by Stephen L. Archer and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-12-06 with Medical categories.

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.

Bk Channels Integrators Of Cellular Signals In Health And Disease

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Author : Thomas M. Weiger
language : en
Publisher: Frontiers Media SA
Release Date : 2017-11-10

Bk Channels Integrators Of Cellular Signals In Health And Disease written by Thomas M. Weiger and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-11-10 with Electronic book categories.

Maxi calcium-activated potassium channels (BK) are an amazing category of ion channels which are found in cellular plasma membranes as well as in membranes of intracellular organelles. The function of these channels is to repolarize any excited membrane by passing a potassium outward current, in response to depolarization and/or increase in local calcium levels. Thus, voltage and calcium ions are involved in gating the channel under physiological conditions. This dual activation makes them perfect sensors for many cellular events that require integration between intracellular calcium levels and electrical signals. A plethora of physiological and pathophysiological functions, such as membrane hyperpolarization, modulation of synaptic transmission, hormone secretion or mental deficiencies, vaso-regulation, epilepsies, heart diseases, myotonic dystrophies, hypertension etc, in almost all cells and tissues were reported for these channels. BK channels are main targets for important ligands like alcohol and gaseous neurotransmitters, such as NO, CO or H2S, to name a few. In the last years, the molecular entities and mechanisms involved in modulation of BK channels have gained tremendous attention, as the key role of these channels in cellular processes became increasingly recognized. Indeed, accessory proteins such as slob, beta and gamma subunits, all serve to modulate the channel gating characteristics. Moreover, channel subunit expression and function is further tuned by phosphorylation/ dephosphorylation processes, redox mechanisms and the lipid microenvironment of the BK channel protein complex. This e-book contains structural and functional aspects of BK channels, channel modulation by a variety of agents and cellular components, as well as the channel’s relevance in health and disease.

Voltage Gated Sodium Channels

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Author : Peter C. Ruben
language : en
Publisher: Springer Science & Business Media
Release Date : 2014-04-15

Voltage Gated Sodium Channels written by Peter C. Ruben and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-04-15 with Medical categories.

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.

Journal Of Comparative Physiology

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Author :
language : en
Publisher:
Release Date : 2002

Journal Of Comparative Physiology written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2002 with Animal behavior categories.