A Large Entrance To The Inner Cavity Of Bk Channels Is Required For Their Large Conductance
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A Large Entrance To The Inner Cavity Of Bk Channels Is Required For Their Large Conductance
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Author :
language : en
Publisher:
Release Date : 2009
A Large Entrance To The Inner Cavity Of Bk Channels Is Required For Their Large Conductance written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009 with categories.
Large conductance voltage and Ca2+ activated K+ (BK) channels control electrical excitability in many cell types. BK channels have the largest conductance (~250 pS) of all K+ selective channels. To explore whether a large entrance to the inner cavity of BK channels is required for their large conductance, I examined if changing the size of the entrance alters the single-channel current amplitude. Previous studies suggest that residues E321/E324 in BK channels are located at the entrance to the inner cavity. To test if positions 321/324 are accessible to intracellular ions, I compared single-channel outward current before and after attaching thiol reagents at E321C/E324C. Attachment of MBB and MTSET altered single-channel currents, indicating that positions 321/324 are accessible to the conduction pathway. Decreasing the size of the entrance to the inner cavity by substituting residues with larger side chains, such as tyrosine and tryptophan, at positions 321/324 decreased the conductance, whereas increasing the size of the entrance had little effect on conductance. Increasing [K+]i from 0.15 to 2.5 M negated differences in single-channel outward current associated with side chain volume. Substitutions had less effect on inward currents. Plots of conductance vs. substituted side chain volume could be approximated with a simple model for the conduction pathway described by two resistors in series, R1 and R2. R2 is a variable resistor, with the resistance proportional to the inverse of the volume of the entrance to the inner cavity not occupied by the side chains. R1 is a fixed resistor arising from the other parts of the conduction pathway including the selectivity filter. Fitting the experimental observations indicated that R1+R2 ~5.4 G &!for glycine substitution, with an R1/R2 ratio of ~17, and an effective radius and length of the entrance to the inner cavity of ~9.0 and 5.4 ¿, respectively. The volume of K+ and water were not taken into account. Taken together, the above observations suggest that a large entrance to the inner cavity is needed for the large conductance of BK channels, as my study shows that the entrance is large and that decreasing the entrance size decreases the currents.
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.
Textbook Of Ion Channels
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Author : Jie Zheng
language : en
Publisher: CRC Press
Release Date : 2023-07-06
Textbook Of Ion Channels written by Jie Zheng and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023-07-06 with Medical categories.
The Textbook of Ion Channels is a set of three volumes providing a wide-ranging reference source on ion channels for students, instructors, and researchers. Ion channels are membrane proteins that control the electrical properties of neurons and cardiac cells, mediate the detection and response to sensory stimuli like light, sound, odor, and taste, and regulate the response to physical stimuli like temperature and pressure. In non-excitable tissues, ion channels are instrumental for the regulation of basic salt balance that is critical for homeostasis. Ion channels are located at the surface membrane of cells, giving them the unique ability to communicate with the environment, as well as the membrane of intracellular organelles, allowing them to regulate internal homeostasis. Ion channels are fundamentally important for human health and diseases, and are important targets for pharmaceuticals in mental illness, heart disease, anesthesia, pain and other clinical applications. The modern methods used in their study are powerful and diverse, ranging from single ion-channel measurement techniques to models of ion channel diseases in animals, and human clinical trials for ion channel drugs. All three volumes give the reader an introduction to fundamental concepts needed to understand the mechanism of ion channels, a guide to the technical aspects of ion channel research, offer a modern guide to the properties of major ion channel families, and include coverage of key examples of regulatory, physiological, and disease roles for ion channels.
Textbook Of Ion Channels Volume I
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Author : Jie Zheng
language : en
Publisher: CRC Press
Release Date : 2023-06-09
Textbook Of Ion Channels Volume I written by Jie Zheng and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023-06-09 with Medical categories.
The Textbook of Ion Channels is a set of three volumes providing a wide-ranging reference source on ion channels for students, instructors and researchers. Ion channels are membrane proteins that control the electrical properties of neurons and cardiac cells; mediate the detection and response to sensory stimuli like light, sound, odor, and taste; and regulate the response to physical stimuli like temperature and pressure. In non-excitable tissues, ion channels are instrumental for the regulation of basic salt balance that is critical for homeostasis. Ion channels are located at the surface membrane of cells, giving them the unique ability to communicate with the environment, as well as the membrane of intracellular organelles, allowing them to regulate internal homeostasis. Ion channels are fundamentally important for human health and diseases, and are important targets for pharmaceuticals in mental illness, heart disease, anesthesia, pain and other clinical applications. The modern methods used in their study are powerful and diverse, ranging from single ion-channel measurement techniques to models of ion channel diseases in animals, and human clinical trials for ion channel drugs. Volume I, Part 1 covers fundamental topics such as the basic principles of ion permeation and selectivity, voltage-dependent, ligand-dependent, and mechano-dependent ion channel activation mechanisms, the mechanisms for ion channel desensitization and inactivation, and basic ion channel pharmacology and inhibition. Volume I, Part 2 offers a practical guide of cardinal methods for researching ion channels, including heterologous expression and voltage-clamp and patch-clamp electrophysiology; isolation of native currents using patch clamping; modeling ion channel gating, structures, and its dynamics; crystallography and cryo-electron microscopy; fluorescence and paramagnetic resonance spectroscopy methods; and genetics approaches in model organisms. All three volumes give the reader an introduction to fundamental concepts needed to understand the mechanism of ion channels; a guide to the technical aspects of ion channel research; a modern guide to the properties of major ion channel families; and includes coverage of key examples of regulatory, physiological and disease roles for ion channels.
Handbook Of Ion Channels
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Author : Jie Zheng
language : en
Publisher: CRC Press
Release Date : 2015-02-25
Handbook Of Ion Channels written by Jie Zheng and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015-02-25 with Medical categories.
The New Benchmark for Understanding the Latest Developments of Ion ChannelsIon 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 ce
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
Molecular Determinants Of Bk Channel Gating And Pharmacology
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Author : Alexandre Vouga
language : en
Publisher:
Release Date : 2021
Molecular Determinants Of Bk Channel Gating And Pharmacology written by Alexandre Vouga and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with categories.
Large conductance Ca2+-activated K+ channels (BK channels) are expressed ubiquitously in both excitable and non-excitable cells and are important for a range of physiological functions. BK channels gate K+ efflux in response to concurrent depolarized membrane voltage and increased intracellular Ca2+ to modulate action potential shape and duration in neurons, regulate contractility in smooth muscle, and control fluid secretion by epithelial cells in the airway and gut. In addition, mutations in the human BK channel gene (KCNMA1) are linked to neurological disease, such as epilepsy and paroxysmal dyskinesia. Thus, BK channel modulators may provide treatment avenues for BK channelopathies. It will be important to expand our arsenal of BK channel-selective activators and inhibitors and to grow our understanding of their molecular mechanisms of action. Discovery of new channel modulators will further lead to a greater understanding of BK channel structure and function. To better understand the basic structure-function relationship of BK channel gating in response to increased intracellular Ca2+ concentration, in this work I initially investigate structural determinants of BK channel activation in response to conformational changes following Ca2+ binding. I analyze crystal structures of the BK channel cytosolic Ca2+-sensing domain (CSD), also known as the "gating ring", formed by the C-terminal domains of each of the four identical pore-forming subunits. In the Ca2+-bound state, N449 from the adjacent subunit contacts the bound Ca2+ ion, forming a "Ca2+ bridge." Mutating N449 to alanine eliminates this coordinate interaction, and using electrophysiology, I found that BK channels with the N449A mutation exhibit a shift in the voltage required for half maximal activation (V1/2) towards more positive voltages. Using size-exclusion chromatography, I observed that the purified BK channel CSD with the N449A mutation shows reduced gating ring oligomerization in response to Ca2+ compared to the wild-type CSD. To further probe molecular determinants of BK channel gating and increase our arsenal of BK channel gating modulators, I optimized a fluorescence-based high throughput screening approach to discover compounds with BK channel inhibitor activity with 99.73% confidence. Through this approach I discovered that the -opioid receptor agonist, loperamide, is a potent BK channel inhibitor. Loperamide (LOP) reduced the open probability of channels at depolarized voltages, but not at very negative voltages when the voltage-sensor is at rest. I observed a weak voltage dependence of loperamide inhibition, consistent with loperamide binding shallow within the inner cavity to block the channel pore. I quantified the inhibitory effect of LOP using an allosteric model in which LOP blocks conduction through open channels and binds with 45-fold higher affinity to the open state over the closed state. These data suggest that loperamide may represent a new class of "use-dependent," open channel blockers. Together this work describes an approach to understanding BK channel structure and function with the goal of identifying and developing novel therapeutics for the treatment of BK-related diseases.
The Oxford Handbook Of Neuronal Ion Channels
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Author : Arin Bhattacharjee
language : en
Publisher: Oxford University Press
Release Date : 2023-01-02
The Oxford Handbook Of Neuronal Ion Channels written by Arin Bhattacharjee and has been published by Oxford University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023-01-02 with categories.
Neurons are excitable cells. They use ions and electrical signaling to talk to each to other and when they talk to each other, neurons control behavior. The Oxford Handbook of Neuronal Ion Channels is an accessible reference describing the nature and properties of ion channels in neurons. The book explains how ion channels open and close, how they can be selective for specific ions, and how they give rise to action potentials. Included are in-depth chapters discussing specific classes of ion channels: potassium channels, sodium channels, neurotransmitter-gated ion channels and other specialized channels. Throughout the handbook, important insight is provided on the contribution ion channels make to neuronal excitability and to synaptic transmission. The handbook goes further to discuss channelopathies, a group of human diseases such as epilepsy, pain and migraines that can be caused by ion channel dysfunction. For neuroscientists, biophysicists and neuropharmacologists, this handbook is a valuable reference of ion channel biology and function.
Patch Clamp Technique
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Author : Fatima Shad Kaneez
language : en
Publisher: BoD – Books on Demand
Release Date : 2012-03-23
Patch Clamp Technique written by Fatima Shad Kaneez and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-03-23 with Science categories.
This book is a stimulating and interesting addition to the collected works on Patch clamp technique. Patch Clamping is an electrophysiological technique, which measures the electric current generated by a living cell, due to the movement of ions through the protein channels present in the cell membrane. The technique was developed by two German scientists, Erwin Neher and Bert Sakmann, who received the Nobel Prize in 1991 in Physiology for this innovative work. Patch clamp technique is used for measuring drug effect against a series of diseases and to find out the mechanism of diseases in animals and plants. It is also most useful in finding out the structure function activities of compounds and drugs, and most leading pharmaceutical companies used this technique for their drugs before bringing them for clinical trial. This book deals with the understanding of endogenous mechanisms of cells and their receptors as well as advantages of using this technique. It covers the basic principles and preparation types and also deals with the latest developments in the traditional patch clamp technique. Some chapters in this book take the technique to a next level of modulation and novel approach. This book will be of good value for students of physiology, neuroscience, cell biology and biophysics.
Alternative Splicing Of Large Conductance Calcium And Voltage Activated Potassium Bk Channels
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Author : Stephen Hsiao-Feng Macdonald
language : en
Publisher:
Release Date : 2006
Alternative Splicing Of Large Conductance Calcium And Voltage Activated Potassium Bk Channels written by Stephen Hsiao-Feng Macdonald and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006 with categories.