Using Synthetic Small Molecules To Probe The Structure And Function Of Voltage Gated Ion Channels

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Using Synthetic Small Molecules to Probe the Structure and Function of Voltage-gated Ion Channels

Author : Justin David Litchfield
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (649 download)

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Book Synopsis Using Synthetic Small Molecules to Probe the Structure and Function of Voltage-gated Ion Channels by : Justin David Litchfield

Download or read book Using Synthetic Small Molecules to Probe the Structure and Function of Voltage-gated Ion Channels written by Justin David Litchfield and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Several methods of examining the structure and function of voltage-gated ion channels are described. The first part of this work involves synthetic small molecules based on the structure of (+)-saxitoxin, a marine neurotoxin. (+)-saxitoxin interacts with the pore of the voltage-gated sodium (NaV) channel to prevent the passage of ions. A scaffold was designed to be modular, synthetically facile, and contain the functionality that had been implicated in the previous literature. Several members of this family of molecules were produced, and they were assayed for occlusion of sodium current (INa). The second part of this work examines the gating kinetics of voltage-gated potassium (KV) channels. 6-bromo-mercaptotryptamine (BrMT) is a marine neurotoxin that has been shown to alter the gating kinetics of KV channels. Specifically, BrMT affects the early, typically independent steps of KV gating by stabilizing the resting state of some number of the subunits. A family of small molecules was designed and synthesized that would examine the functional effects of different parts of the BrMT molecule. BrMT is a dimer containing three key functional groups: a halogenated indole, a pendant ethyl-amine, and a disulfide linker. Variance at all these positions was examined, and each had different effects. Notably, one of the variants, in which the disulfide linker was substituted for an oxy-bismethyl ether linker, affects KV gating in a different way from BrMT. Alternate models of gating in the presence of this novel analog are discussed.

Ion Channels: Channel Chemical Biology, Engineering, and Physiological Function

Author :
Publisher : Academic Press
ISBN 13 : 0128239255
Total Pages : 454 pages
Book Rating : 4.1/5 (282 download)

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Book Synopsis Ion Channels: Channel Chemical Biology, Engineering, and Physiological Function by :

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

Structure, Function, and Modulation of Neuronal Voltage-Gated Ion Channels

Author : Valentin K. Gribkoff
Publisher : Wiley
ISBN 13 : 9780471930136
Total Pages : 0 pages
Book Rating : 4.9/5 (31 download)

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Book Synopsis Structure, Function, and Modulation of Neuronal Voltage-Gated Ion Channels by : Valentin K. Gribkoff

Download or read book Structure, Function, and Modulation of Neuronal Voltage-Gated Ion Channels written by Valentin K. Gribkoff and published by Wiley. This book was released on 2009-02-03 with total page 0 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.

Development of Small Molecule Ligands for Voltage-gated Potassium Channels and Functional Characterization of Voltage-gated Phosphatases

Download Development of Small Molecule Ligands for Voltage-gated Potassium Channels and Functional Characterization of Voltage-gated Phosphatases PDF Online Free

Author : Sarah C. Bell
Publisher :
ISBN 13 :
Total Pages : 384 pages
Book Rating : 4.:/5 (81 download)

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Book Synopsis Development of Small Molecule Ligands for Voltage-gated Potassium Channels and Functional Characterization of Voltage-gated Phosphatases by : Sarah C. Bell

Download or read book Development of Small Molecule Ligands for Voltage-gated Potassium Channels and Functional Characterization of Voltage-gated Phosphatases written by Sarah C. Bell and published by . This book was released on 2010 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: Membrane proteins respond to both chemical and electrical stimuli. This work explores the molecular mechanisms by which membrane voltage controls voltage-gated proteins and describes the development of tools to modulate voltage-gated protein function. Voltage-gated potassium (Kv) channels are tetrameric transmembrane proteins that translate changes in the membrane electric field into the controlled permeation of potassium across the plasma membrane. Kv channels mediate the initiation and regulation of action potentials, muscle contraction, hormone secretion, and information processing, rendering them important drug targets. We employed organic synthesis, molecular dynamics and electrophysiology techniques to demonstrate that calix[4]arenes with free phenolic OH groups at the lower rim and positively-charged groups at the upper rim constitute a versatile class of reversible ligands for homotetrameric Kv1.x channels. Synthesis of a panel of calix[4]arenes with variable upper and lower rim substituents enabled the systematic development of Kv1.x channel-compatible ligands. We used molecular modeling to predict calix[4]arene binding to the pore domain, and through electrophysiology experiments, we demonstrated that the calix[4]arene ligands function as reversible blockers of Kv1.x channels. We probed the mechanism of calix[4]arene-channel interactions using voltage clamp fluorometry and found these ligands modify the voltage-dependent motions of the Shaker Kv channel in addition to inhibiting ion current. These calix[4]arene ligands provide a new set of tools to control cell excitability by specifically targeting Kv channels. Until recently, ion channels were the only proteins known to sense changes in membrane potential. This changed with the discovery of Ciona intestinalis voltage-sensor containing phosphatase (Ci-VSP) which has a voltage sensing domain like voltage-gated ion channels and a cytosolic phosphatase domain resembling the phosphoinositide phosphatase PTEN. Ci-VSP is the first member of the voltage dependent family of proteins that is not an ion channel. Instead, Ci-VSP takes an electrical signal in the form of membrane voltage and converts it to a chemical signal through its phosphatase activity. To study the mechanism of voltage-sensing in Ci-VSP, we combined electrophysiology and fluorescence methods in living cells to determine the oligomerization state of Ci-VSP and monitor the functional transitions that result in Ci-VSP mediated changes in phosphoinositide pools. We find that Ci-VSP is a functional monomer which undergoes complex voltage-dependent conformational changes to control a cytosolic phosphoinositide phosphatase domain. As Ci-VSP catalyzes several reactions, we also developed fluorescent-based methods to study Ci-VSP substrate specificity and monitor Ci-VSP-mediated changes in multiple phosphoinositide pools in a single cell. Finally, we find that basic residues in the interdomain linker connecting the voltage sensing domain and phosphatase domains in Ci-VSP are essential for coupling the two domains. Our results indicate that a single voltage sensing domain can function in the membrane on its own and suggests that voltage sensing domains are modular units that can impart voltage sensitivity to a variety of effector domains.

Voltage Gated Sodium Channels

Author : Peter C. Ruben
Publisher : Springer Science & Business Media
ISBN 13 : 3642415881
Total Pages : 328 pages
Book Rating : 4.6/5 (424 download)

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Book Synopsis Voltage Gated Sodium Channels by : Peter C. Ruben

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.

Ion Channels and Disease

Author : Frances M. Ashcroft
Publisher : Academic Press
ISBN 13 : 0080535216
Total Pages : 505 pages
Book Rating : 4.0/5 (85 download)

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Book Synopsis Ion Channels and Disease by : Frances M. Ashcroft

Download or read book Ion Channels and Disease written by Frances M. Ashcroft and published by Academic Press. This book was released on 1999-10-20 with total page 505 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion channels are membrane proteins that act as gated pathways for the movement of ions across cell membranes. They play essential roles in the physiology of all cells. In recent years, an ever-increasing number of human and animal diseases have been found to result from defects in ion channel function. Most of these diseases arise from mutations in the genes encoding ion channel proteins, and they are now referred to as the channelopathies. Ion Channels and Disease provides an informative and up-to-date account of our present understanding of ion channels and the molecular basis of ion channel diseases. It includes a basic introduction to the relevant aspects of molecular biology and biophysics and a brief description of the principal methods used to study channelopathies. For each channel, the relationship between its molecular structure and its functional properties is discussed and ways in which genetic mutations produce the disease phenotype are considered. This book is intended for research workers and clinicians, as well as graduates and advanced undergraduates. The text is clear and lively and assumes little knowledge, yet it takes the reader to frontiers of what is currently known about this most exciting and medically important area of physiology. - Introduces the relevant aspects of molecular biology and biophysics - Describes the principal methods used to study channelopathies - Considers single classes of ion channels with summaries of the physiological role, subunit composition, molecular structure and chromosomal location, plus the relationship between channel structure and function - Looks at those diseases associated with defective channel structures and regulation, including mutations affecting channel function and to what extent this change in channel function can account for the clinical phenotype

Ion Channel Drug Discovery

Author : Brian Cox
Publisher : Royal Society of Chemistry
ISBN 13 : 1849735085
Total Pages : 385 pages
Book Rating : 4.8/5 (497 download)

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Book Synopsis Ion Channel Drug Discovery by : Brian Cox

Download or read book Ion Channel Drug Discovery written by Brian Cox and published by Royal Society of Chemistry. This book was released on 2014-09-03 with total page 385 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion channel drug discovery is a rapidly evolving field fuelled by recent, but significant, advances in our understanding of ion channel function combined with enabling technologies such as automated electrophysiology. The resurgent interest in this target class by both pharmaceutical and academic scientists was clearly highlighted by the over-subscribed RSC/BPS 'Ion Channels as Therapeutic Targets' symposium in February 2009. This book builds on the platform created by that meeting, covering themes including advances in screening technology, ion channel structure and modelling and up-to-date case histories of the discovery of modulators of a range of channels, both voltage-gated and non-voltage-gated channels. The editors have built an extensive network of contacts in the field through their first-hand scientific experience, collaborations and conference participation and the organisation of the meeting at Novartis, Horsham, increased the network enabling the editors to draw on the experience of eminent researchers in the field. Interest and investment in ion channel modulation in both industrial and academic settings continues to grow as new therapeutic opportunities are identified and realised for ion channel modulation. This book provides a reference text by covering a combination of recent advances in the field, from technological and medicinal chemistry perspectives, as well as providing an introduction to the new 'ion channel drug discoverer'. The book has contributions from highly respected academic researchers, industrial researchers at the cutting edge of drug discovery and experts in enabling technology. This combination provides a complete picture of the field of interest to a wide range of readers.

Voltage-Gated Ion Channels as Drug Targets

Author : David J. Triggle
Publisher : John Wiley & Sons
ISBN 13 : 3527607749
Total Pages : 492 pages
Book Rating : 4.5/5 (276 download)

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Book Synopsis Voltage-Gated Ion Channels as Drug Targets by : David J. Triggle

Download or read book Voltage-Gated Ion Channels as Drug Targets written by David J. Triggle and published by John Wiley & Sons. This book was released on 2006-08-21 with total page 492 pages. Available in PDF, EPUB and Kindle. Book excerpt: Edited by the most prominent person in the field and top researchers at US pharmaceutical companies, this is a unique resource for drug developers and physiologists seeking a molecular-level understanding of ion channel pharmacology. After an introduction to the topic, the authors evaluate the structure and function of ion channels, as well as related drug interaction. A section on assay technologies is followed by a section each on calcium, sodium and potassium channels. Further chapters cover genetic and acquired channelopathies, before the book closes with a look at safety issues in ion channel drug development. For medicinal and pharmaceutical chemists, biochemists, molecular biologists and those working in the pharmaceutical industry.

Analytical Methods in Supramolecular Chemistry

Author : Christoph A. Schalley
Publisher : John Wiley & Sons
ISBN 13 : 3527644148
Total Pages : 849 pages
Book Rating : 4.5/5 (276 download)

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Book Synopsis Analytical Methods in Supramolecular Chemistry by : Christoph A. Schalley

Download or read book Analytical Methods in Supramolecular Chemistry written by Christoph A. Schalley and published by John Wiley & Sons. This book was released on 2012-09-25 with total page 849 pages. Available in PDF, EPUB and Kindle. Book excerpt: The second edition of "Analytical Methods in Supramolecular Chemistry" comes in two volumes and covers a broad range of modern methods and techniques now used for investigating supramolecular systems, e. g. NMR spectroscopy, mass spectrometry, extraction methods, crystallography, single molecule spectroscopy, electrochemisty, and many more. In this second edition, tutorial inserts have been introduced, making the book also suitable as supplementary reading for courses on supramolecular chemistry. All chapters have been revised and updated and four new chapters have been added. A must-have handbook for Organic and Analytical Chemists, Spectroscopists, Materials Scientists, and Ph.D. Students in Chemistry. From reviews of the first edition: "This timely book should have its place in laboratories dealing with supramolecular objects. It will be a source of reference for graduate students and more experienced researchers and could induce new ideas on the use of techniques other than those usually used in the laboratory." Journal of the American Chemical Society (2008) VOL. 130, NO. 1 doi: 10.1021/ja0769649 "The book as a whole or single chapters will stimulate the reader to widen his horizon in chemistry and will help him to have new ideas in his research." Anal Bioanal Chem (2007) 389:2039-2040 DOI: 10.1007/s00216-007-1677-1

Voltage-gated Sodium Channels: Structure, Function and Channelopathies

Author : Mohamed Chahine
Publisher : Springer
ISBN 13 : 3319902849
Total Pages : 448 pages
Book Rating : 4.3/5 (199 download)

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Book Synopsis Voltage-gated Sodium Channels: Structure, Function and Channelopathies by : Mohamed Chahine

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 448 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.

Ionic Channels of Excitable Membranes

Author : Bertil Hille
Publisher : Sinauer Associates, Incorporated
ISBN 13 :
Total Pages : 638 pages
Book Rating : 4.3/5 (91 download)

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Book Synopsis Ionic Channels of Excitable Membranes by : Bertil Hille

Download or read book Ionic Channels of Excitable Membranes written by Bertil Hille and published by Sinauer Associates, Incorporated. This book was released on 1992 with total page 638 pages. Available in PDF, EPUB and Kindle. Book excerpt: This new, fully revised and expanded edition of Ionic Channels of Excitable Membranes includes new chapters on fast chemical synapses, modulation through G protein coupled receptors and second messenger systems, molecules cloning, site directed mutagenesis, and cell biology. It begins with the classical biophysical work of Hodgkin and Huxley and then weaves a description of the known ionic channels together with their biological functions. The book continues by developing the physical and molecular principles needed for explaining permeation, gating, pharmacological modification, and molecular diversity, and ends with a discussion of channel evolution. Ionic Channels of Excitable Membranes is written to be accessible and interesting to biological and physical scientists of all kinds.

Small Molecule Microarrays: Methods and Protocols

Author : Mahesh Uttamchandani
Publisher : Methods in Molecular Biology
ISBN 13 : 9781493982424
Total Pages : 274 pages
Book Rating : 4.9/5 (824 download)

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Book Synopsis Small Molecule Microarrays: Methods and Protocols by : Mahesh Uttamchandani

Download or read book Small Molecule Microarrays: Methods and Protocols written by Mahesh Uttamchandani and published by Methods in Molecular Biology. This book was released on 2018-12-05 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Physics of Ionic Conduction in Narrow Biological and Artificial Channels- Publish

Author : Peter V E McClintock
Publisher : Mdpi AG
ISBN 13 : 9783036516462
Total Pages : 306 pages
Book Rating : 4.5/5 (164 download)

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Book Synopsis Physics of Ionic Conduction in Narrow Biological and Artificial Channels- Publish by : Peter V E McClintock

Download or read book Physics of Ionic Conduction in Narrow Biological and Artificial Channels- Publish written by Peter V E McClintock and published by Mdpi AG. This book was released on 2021-09-23 with total page 306 pages. Available in PDF, EPUB and Kindle. Book excerpt: The book reprints a set of important scientific papers applying physics and mathematics to address the problem of selective ionic conduction in narrow water-filled channels and pores. It is a long-standing problem, and an extremely important one. Life in all its forms depends on ion channels and, furthermore, the technological applications of artificial ion channels are already widespread and growing rapidly. They include desalination, DNA sequencing, energy harvesting, molecular sensors, fuel cells, batteries, personalised medicine, and drug design. Further applications are to be anticipated. The book will be helpful to researchers and technologists already working in the area, or planning to enter it. It gives detailed descriptions of a diversity of modern approaches, and shows how they can be particularly effective and mutually reinforcing when used together. It not only provides a snapshot of current cutting-edge scientific activity in the area, but also offers indications of how the subject is likely to evolve in the future.

Small Molecule Medicinal Chemistry

Author : Werngard Czechtizky
Publisher : John Wiley & Sons
ISBN 13 : 1118771575
Total Pages : 528 pages
Book Rating : 4.1/5 (187 download)

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Book Synopsis Small Molecule Medicinal Chemistry by : Werngard Czechtizky

Download or read book Small Molecule Medicinal Chemistry written by Werngard Czechtizky and published by John Wiley & Sons. This book was released on 2015-09-21 with total page 528 pages. Available in PDF, EPUB and Kindle. Book excerpt: Stressing strategic and technological solutions to medicinal chemistry challenges, this book presents methods and practices for optimizing the chemical aspects of drug discovery. Chapters discuss benefits, challenges, case studies, and industry perspectives for improving drug discovery programs with respect to quality and costs. • Focuses on small molecules and their critical role in medicinal chemistry, reviewing chemical and economic advantages, challenges, and trends in the field from industry perspectives • Discusses novel approaches and key topics, like screening collection enhancement, risk sharing, HTS triage, new lead finding approaches, diversity-oriented synthesis, peptidomimetics, natural products, and high throughput medicinal chemistry approaches • Explains how to reduce design-make-test cycle times by integrating medicinal chemistry, physical chemistry, and ADME profiling techniques • Includes descriptive case studies, examples, and applications to illustrate new technologies and provide step-by-step explanations to enable them in a laboratory setting

Molecular Biology of the Cell

Author :
Publisher :
ISBN 13 : 9780815332183
Total Pages : 0 pages
Book Rating : 4.3/5 (321 download)

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Book Synopsis Molecular Biology of the Cell by :

Download or read book Molecular Biology of the Cell written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Structure and Dynamics of Confined Polymers

Author : John J. Kasianowicz
Publisher : Springer Science & Business Media
ISBN 13 : 9781402006975
Total Pages : 46 pages
Book Rating : 4.0/5 (69 download)

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Book Synopsis Structure and Dynamics of Confined Polymers by : John J. Kasianowicz

Download or read book Structure and Dynamics of Confined Polymers written by John J. Kasianowicz and published by Springer Science & Business Media. This book was released on 2002-07-31 with total page 46 pages. Available in PDF, EPUB and Kindle. Book excerpt: Polymers are essential to biology because they can have enough stable degrees of freedom to store the molecular code of heredity and to express the sequences needed to manufacture new molecules. Through these they perform or control virtually every function in life. Although some biopolymers are created and spend their entire career in the relatively large free space inside cells or organelles, many biopolymers must migrate through a narrow passageway to get to their targeted destination. This suggests the questions: How does confining a polymer affect its behavior and function? What does that tell us about the interactions between the monomers that comprise the polymer and the molecules that confine it? Can we design and build devices that mimic the functions of these nanoscale systems? The NATO Advanced Research Workshop brought together for four days in Bikal, Hungary over forty experts in experimental and theoretical biophysics, molecular biology, biophysical chemistry, and biochemistry interested in these questions. Their papers collected in this book provide insight on biological processes involving confinement and form a basis for new biotechnological applications using polymers. In his paper Edmund DiMarzio asks: What is so special about polymers? Why are polymers so prevalent in living things? The chemist says the reason is that a protein made of N amino acids can have any of 20 different kinds at each position along the chain, resulting in 20 N different polymers, and that the complexity of life lies in this variety.

Potassium Channels in Cardiovascular Biology

Author : Stephen L. Archer
Publisher : Springer Science & Business Media
ISBN 13 : 9780306464027
Total Pages : 962 pages
Book Rating : 4.4/5 (64 download)

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Book Synopsis Potassium Channels in Cardiovascular Biology by : Stephen L. Archer

Download or read book Potassium Channels in Cardiovascular Biology written by Stephen L. Archer and published by Springer Science & Business Media. This book was released on 2001-05-31 with total page 962 pages. Available in PDF, EPUB and Kindle. Book excerpt: Potassium channels (K+) are membrane-spanning proteins which serve many important functions and are a hotly debated topic in physiology. This book highlights the latest discoveries on the role of K+ channels in the heart and blood vessels in normal physiology and a variety of disease states.