Molecular Determinants Of Bk Channel Gating And Pharmacology

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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.

Molecular Determinants Of Different Gating Mechanisms In Inwardly Rectifying Potassium Channels

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Author : Xinyang Huang
language : en
Publisher:
Release Date : 2012

Molecular Determinants Of Different Gating Mechanisms In Inwardly Rectifying Potassium Channels written by Xinyang Huang and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012 with categories.

Molecular Determinants Of Gating At The Potassium Channel Selectivity Filter

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Author : Julio F. Cordero-Morales
language : en
Publisher:
Release Date : 2008

Molecular Determinants Of Gating At The Potassium Channel Selectivity Filter written by Julio F. Cordero-Morales and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008 with categories.

Abstract not available.

Molecular Determinants For Gating Of Kv Channels

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Author : Alain J. Labro
language : en
Publisher:
Release Date : 2005

Molecular Determinants For Gating Of Kv Channels written by Alain J. Labro and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2005 with categories.

Pharmacology Of Potassium Channels

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Author : Nikita Gamper
language : en
Publisher: Springer Nature
Release Date : 2021-09-27

Pharmacology Of Potassium Channels written by Nikita Gamper and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021-09-27 with Medical categories.

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.

Handbook Of Nutrition Diet And The Eye

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Author : Victor R. Preedy
language : en
Publisher: Academic Press
Release Date : 2019-06-11

Handbook Of Nutrition Diet And The Eye written by Victor R. Preedy and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019-06-11 with Medical categories.

Handbook of Nutrition, Diet, and the Eye, Second Edition, thoroughly addresses common features and etiological factors on how dietary and nutritional factors affect the eye. The ocular system is perhaps one of the least studied organs in diet and nutrition, yet the consequences of vision loss are devastating. There are a range of ocular defects that have either their origin in nutritional deficiencies/excess or have been shown to respond favorably to nutritional components. Featuring a new section on animal model studies where both the ocular problem and dietary remedies can be varied, there are also new chapters on dietary supplements. Serves as a foundational collection for neuroscience, neurology and nutrition researchers, illustrating the importance of nutrition and diet in eye health and function Provides a common language for readers to discuss how nutritional factors and related diseases and syndromes affect the eye Features new chapters on infectious diseases of the eye where nutrition is a factor Discusses animal model studies, dietary supplements, natural dietary extracts from around the world, and age-related changes in ocular health

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.

Molecular Mechanisms Of Voltage Gating In Ion Channels

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Author : Gildas Loussouarn
language : en
Publisher: Frontiers Media SA
Release Date : 2021-11-03

Molecular Mechanisms Of Voltage Gating In Ion Channels written by Gildas Loussouarn 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 2021-11-03 with Science categories.

Molecular Physiology And Pharmacology Of Cardiac Ion Channels And Transporters

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Author : M. Morad
language : en
Publisher: Springer Science & Business Media
Release Date : 2012-12-06

Molecular Physiology And Pharmacology Of Cardiac Ion Channels And Transporters written by M. Morad 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.

Knowledge of cardiac ion channels and transporters has advanced remarkably in the last two decades with the development of patch-clamp and molecular biological techniques. This textbook offers a comprehensive overview of structures and functions of ion channels and transporters in the heart. Readers are first introduced to the molecular biology and electrophysiology of all the important ion channels. After discussing their developmental changes, the pharmacology and pathophysiology of clinically-relevant ion channels are reviewed. Molecular aspects of the cardiac excitation-contraction coupling and intracellular Ca2+ regulation by ion transporters are also described. The book will be useful to electrophysiologists, cardiac physiologists and pharmacologists, and molecular biologists interested in ion channels at all levels. For research specialists, the book will provide a perspective of the field. The book can be used as a reference source for working scientists in the fields of ion channels, biophysics, cardiac electrophysiology, and pharmacology. It is aimed at graduate and medical students, designed for use as a textbook for graduate and medical courses.

Pharmacological Aspects Of Ligand Gated Ion Channels As Targets Of Natural And Synthetic Agents

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Author : César Mattei
language : en
Publisher: Frontiers Media SA
Release Date : 2022-05-11

Pharmacological Aspects Of Ligand Gated Ion Channels As Targets Of Natural And Synthetic Agents written by César Mattei 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 2022-05-11 with Science categories.