Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels
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Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels
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Author : Malin Silverå Ejneby
language : en
Publisher: Linköping University Electronic Press
Release Date : 2018-05-15
Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels written by Malin Silverå Ejneby and has been published by Linköping University Electronic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-05-15 with Cell membranes categories.
Voltage-gated ion channels are pore-forming membrane proteins that open or close their gates when the voltage across the membrane is changed. They underlie the electrical activity that enables the heart to pump blood and the brain to receive and send signals. Changes in expression, distribution, and functional properties of voltage-gated ion channels can lead to diseases, such as epilepsy, cardiac arrhythmia, and pain-related disorders. Drugs that modulate the function of voltage-gated ion channels control these diseases in some patients, but the existing drugs do not adequately help all patients, and some also have severe side effects. Resin acids are common components of pine resins, with a hydrophobic three-ringed motif and a negatively charged carboxyl group. They open big-conductance Ca2+-activated K+ (BK) channels and voltage-gated potassium (KV) channels. We aimed to characterize the binding site and mechanism of action of resin acids on a KV channel and explore the effect of a resin acid by modifying the position and valence of charge of the carboxyl group. We tested the effect on several voltage-gated ion channels, including two KV channels expressed in Xenopus laevis oocytes and several voltage-gated ion channels expressed in cardiomyocytes. For this endeavour different electrophysiological techniques, ion channels, and cell types were used together with chemical synthesis of about 140 resin-acid derivatives, mathematical models, and computer simulations. We found that resin acids bind between the lipid bilayer and the Shaker KV channel, in the cleft between transmembrane segment S3 and S4, on the extracellular side of the voltage-sensor domain. This is a fundamentally new interaction site for small-molecule compounds that otherwise usually bind to ion channels in pockets surrounded by water. We also showed that the resin acids open the Shaker KV channel via an electrostatic mechanism, exerted on the positively charged voltage sensor S4. The effect of a resin acid increased when the negatively charged carboxyl group (the effector) and the hydrophobic three-ringed motif (anchor in lipid bilayer) were separated by three atoms: longer stalks decreased the effect. The length rule, in combination with modifications of the anchor, was used to design new resin-acid derivatives that open the human M-type (Kv7.2/7.3) channel. A naturally occurring resin acid also reduced the excitability of cardiomyocytes by affecting the voltage-dependence of several voltage-gated ion channels. The major finding was that the resin acid inactivated sodium and calcium channels, while it activated KV channels at more negative membrane voltages. Computer simulations confirmed that the combined effect on different ion channels reduced the excitability of a cardiomyocyte. Finally, the resin acid reversed induced arrhythmic firing of the cardiomyocytes. In conclusion, resin acids are potential drug candidates for diseases such as epilepsy and cardiac arrhythmia: knowing the binding site and mechanism of action can help to fine tune the resin acid to increase the effect, as well as the selectivity.
Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels
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Author : Malin Silverå Ejneby
language : en
Publisher:
Release Date : 2018
Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels written by Malin Silverå Ejneby and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
Voltage-gated ion channels are pore-forming membrane proteins that open or close their gates when the voltage across the membrane is changed. They underlie the electrical activity that enables the heart to pump blood and the brain to receive and send signals. Changes in expression, distribution, and functional properties of voltage-gated ion channels can lead to diseases, such as epilepsy, cardiac arrhythmia, and pain-related disorders. Drugs that modulate the function of voltage-gated ion channels control these diseases in some patients, but the existing drugs do not adequately help all patients, and some also have severe side effects. Resin acids are common components of pine resins, with a hydrophobic three-ringed motif and a negatively charged carboxyl group. They open big-conductance Ca2+-activated K+ (BK) channels and voltage-gated potassium (KV) channels. We aimed to characterize the binding site and mechanism of action of resin acids on a KV channel and explore the effect of a resin acid by modifying the position and valence of charge of the carboxyl group. We tested the effect on several voltage-gated ion channels, including two KV channels expressed in Xenopus laevis oocytes and several voltage-gated ion channels expressed in cardiomyocytes. For this endeavour different electrophysiological techniques, ion channels, and cell types were used together with chemical synthesis of about 140 resin-acid derivatives, mathematical models, and computer simulations. We found that resin acids bind between the lipid bilayer and the Shaker KV channel, in the cleft between transmembrane segment S3 and S4, on the extracellular side of the voltage-sensor domain. This is a fundamentally new interaction site for small-molecule compounds that otherwise usually bind to ion channels in pockets surrounded by water. We also showed that the resin acids open the Shaker KV channel via an electrostatic mechanism, exerted on the positively charged voltage sensor S4. The effect of a resin acid increased when the negatively charged carboxyl group (the effector) and the hydrophobic three-ringed motif (anchor in lipid bilayer) were separated by three atoms: longer stalks decreased the effect. The length rule, in combination with modifications of the anchor, was used to design new resin-acid derivatives that open the human M-type (Kv7.2/7.3) channel. A naturally occurring resin acid also reduced the excitability of cardiomyocytes by affecting the voltage-dependence of several voltage-gated ion channels. The major finding was that the resin acid inactivated sodium and calcium channels, while it activated KV channels at more negative membrane voltages. Computer simulations confirmed that the combined effect on different ion channels reduced the excitability of a cardiomyocyte. Finally, the resin acid reversed induced arrhythmic firing of the cardiomyocytes. In conclusion, resin acids are potential drug candidates for diseases such as epilepsy and cardiac arrhythmia: knowing the binding site and mechanism of action can help to fine tune the resin acid to increase the effect, as well as the selectivity.
Molecular Mechanisms Of Resin Acids And Their Derivatives On The Opening Of A Potassium Channel
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Author : Nina Ottosson
language : en
Publisher: Linköping University Electronic Press
Release Date : 2017-04-20
Molecular Mechanisms Of Resin Acids And Their Derivatives On The Opening Of A Potassium Channel written by Nina Ottosson and has been published by Linköping University Electronic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-04-20 with categories.
Voltage-gated ion channels play fundamental roles in excitable cells, such as neurons, where they enable electric signaling. Normally, this signaling is well controlled, but brain damage, alterations in the ionic composition of the extracellular solution, or dysfunctional ion channels can increase the electrical excitability thereby causing epilepsy. Voltage-gated ion channels are obvious targets for antiepileptic drugs, and, as a rule of thumb, excitability is dampened either by closing voltagegated sodium channels (Nav channels) or by opening voltage-gated potassium channels (Kv channels). For example, several classical antiepileptic drugs block the ion-conducting pore of Nav channels. Despite the large number of existing antiepileptic drugs, one third of the patients with epilepsy suffer from intractable or pharmacoresistant seizures. Our research group has earlier described how different polyunsaturated fatty acids (PUFAs) open a Kv channel by binding close to the voltage sensor and, from this position, electrostatically facilitate the movement of the voltage-sensor, thereby opening the channel. However, PUFAs affect a wide range of ion channels, making it difficult to use them as pharmaceutical drugs; it would be desirable to find smallmolecule compounds with an electrostatic, PUFA-like mechanism of action. The aim of the research leading to this thesis was to find, characterize, and refine drug candidates capable of electrostatically opening a Kv channel. The majority of the experiments were performed on the cloned Shaker Kv channel, expressed in oocytes from the frog Xenopus laevis, and the channel activity was explored with the two-electrode voltage-clamp technique. By systematically mutating the extracellular end of the channel’s voltage sensor, we constructed a highly PUFAsensitive channel, called the 3R channel. Such a channel is a useful tool in the search for electrostatic Kv-channel openers. We found that resin acids, naturally occurring in tree resins, act as electrostatic Shaker Kv channel openers. To explore the structure-activity relationship in detail, we synthesized 120 derivatives, whereof several were potent Shaker Kv channel openers. We mapped a common resin acidbinding site to a pocket formed by the voltage sensor, the channel’s third transmembrane segment, and the lipid membrane, a principally new binding site for small-molecule compounds. Further experiments showed that there are specific interactions between the compounds and the channel, suggesting promises for further drug development. Several of the most potent Shaker Kv channel openers also dampened the excitability in dorsal-root-ganglion neurons from mice, elucidating the pharmacological potency of these compounds. In conclusion, we have found that resin-acid derivatives are robust Kv-channel openers and potential drug candidates against diseases caused by hyperexcitability, such as epilepsy.
Index Medicus
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Author :
language : en
Publisher:
Release Date : 2004
Index Medicus written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004 with Medicine categories.
Vols. for 1963- include as pt. 2 of the Jan. issue: Medical subject headings.
Principles And Practice Of Phytotherapy E Book
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Author : Kerry Bone
language : en
Publisher: Elsevier Health Sciences
Release Date : 2013-01-08
Principles And Practice Of Phytotherapy E Book written by Kerry Bone 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 2013-01-08 with Medical categories.
The authoritative and comprehensive modern textbook on western herbal medicine - now in its second edition This long-awaited second edition of Principles and Practice of Phytotherapy covers all major aspects of herbal medicine from fundamental concepts, traditional use and scientific research through to safety, effective dosage and clinical applications. Written by herbal practitioners with active experience in clinical practice, education, manufacturing and research, the textbook is both practical and evidence based. The focus, always, is on the importance of tailoring the treatment to the individual case. New insights are given into the herbal management of approxiately 100 modern ailments, including some of the most challenging medical conditions, such as asthma, inflammatory bowel disease and other complex autoimmune and inflammatory conditions, and there is vibrant discussion around the contribution of phytotherapy in general to modern health issues, including health ageing. Fully referenced throughout, with more than 10, 000 citations, the book is a core resource for students and practitioners of phytotherapy and naturopathy and will be of value to all healthcare professionals - pharmacists, doctors, nurses - with an interest in herbal therapeutics. 50 evidence-based monographs, including 7 new herbs Rational guidance to phytotherapeutic strategies in the consulting room New appendices provide useful information on topics such as herbal actions, dosage in children and reading and interpreting herbal clinical trials Comprehensive revision of vital safety data, including an extensive herb-drug interaction chart. 50 evidence-based monographs, including 7 new herbs Rational guidance to phytotherapeutic strategies in the consulting room New appendices provide useful information on topics such as herbal actions, dosage in children and reading and interpreting herbal clinical trials Comprehensive revision of vital safety data, including an extensive herb-drug interaction chart.
Biomembrane Electrochemistry
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Author : Martin Blank
language : en
Publisher:
Release Date : 1994
Biomembrane Electrochemistry written by Martin Blank and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1994 with Science categories.
In October 1986, the Office of Naval Research initiated a five-year program for electrochemical research on biological and model membranes. The program explored the physical basis of biological sensory and energy-transducing processes by focusing on the electrochemical properties of integral membrane proteins (i.e., channel structures) associated with ion-transport processes. The major research areas covered were interfaces and lipid layers, channels (structure and function), and signal transduction. This volume contains papers from that program as well as some related studies. Annotation copyright by Book News, Inc., Portland, OR
Chemical Abstracts
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Author :
language : en
Publisher:
Release Date : 2002
Chemical Abstracts 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 Chemistry categories.
Cumulated Index Medicus
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Author :
language : en
Publisher:
Release Date : 2000
Cumulated Index Medicus written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2000 with Medicine categories.
Concise Dictionary Of Pharmacological Agents
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Author : Dr. Ian Morton
language : en
Publisher: Springer Science & Business Media
Release Date : 1999-10-31
Concise Dictionary Of Pharmacological Agents written by Dr. Ian Morton 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 1999-10-31 with Medical categories.
This dictionary provides a convenient personal reference source, intended to complement more encyclopaedic works. First, there is an alphabetic, fully cross-indexed listing of pharmacologically active agents and their properties, containing details of some 4000 individual chemical agents including medical drugs in current use, experimental agents and toxins used as investigation tools. Over 10,000 alternative names are indexed, including chemical names, abbreviated chemical names, official pharmacological names, proprietary names and research code numbers. A key feature is that the properties of the agents are categorised, according to mechanism and use, into 300 classes -for each of which there are descriptive articles for which key literature and review references are provided. Second, there is an alphabetical glossary explaining the meaning of some 3000 biomedical terms from pharmacology, biochemistry, molecular biology, immunology, pathology, physiology, anatomy and microbiology. Emphasis in explanation is given to terms that can cause confusion, for example those relating to drug receptors and to endogenous mediators. Audience: This work provides indispensable information for researchers in the fields of pharmacology, medicinal chemistry and pharmaceutics, and biochemistry, as well as for medical and science writers and editors and drug regulatory officers.
Wiley Encyclopedia Of Chemical Biology Volume 4
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Author : Tadhg P. Begley
language : en
Publisher: Wiley-Blackwell
Release Date : 2009-02-03
Wiley Encyclopedia Of Chemical Biology Volume 4 written by Tadhg P. Begley and has been published by Wiley-Blackwell this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-02-03 with Science categories.
The first major reference at the interface of chemistry, biology, and medicine Chemical biology is a rapidly developing field that uses the principles, tools, and language of chemistry to answer important questions in the life sciences. It has enabled researchers to gather critical information about the molecular biology of the cell and is the fundamental science of drug discovery, playing a key role in the development of novel agents for the prevention, diagnosis, and treatment of disease. Now students and researchers across the range of disciplines that use chemical biology techniques have a single resource that encapsulates what is known in the field. It is an excellent place to begin any chemical biology investigation. Major topics addressed in the encyclopedia include: Applications of chemical biology Biomolecules within the cell Chemical views of biology Chemistry of biological processes and systems Synthetic molecules as tools for chemical biology Technologies and techniques in chemical biology Some 300 articles range from pure basic research to areas that have immediate applications in fields such as drug discovery, sensor technology, and catalysis. Novices in the field can turn to articles that introduce them to the basics, whereas experienced researchers have access to articles exploring the cutting edge of the science. Each article ends with a list of references to facilitate further investigation. With contributions from leading researchers and pioneers in the field, the Wiley Encyclopedia of Chemical Biology builds on Wiley's unparalleled reputation for helping students and researchers understand the crucial role of chemistry and chemical techniques in the life sciences.
