Publisher: Springer Science & Business Media
ISBN: 9781402055256
Size: 56.26 MB
Format: PDF, ePub, Docs
Category : Science
Languages : en
Pages : 532
View: 3046
Book Description: Voltage-sensitive ion channels are macromolecules embedded in the membranes of nerve and muscle fibers of animals. Despite decades of intensive research under the traditional approach of gated structural pores, the relation between the structure of these molecules and their function remains enigmatic. This book examines physically oriented approaches not covered in other ion-channel books, and it develops a new physics-based approach to the problem of molecular excitability.
Voltage Gated Ion Channels As Drug Targets
Author: David J. Triggle
Publisher: John Wiley & Sons
ISBN: 3527607749
Size: 44.70 MB
Format: PDF, Mobi
Category : Science
Languages : en
Pages : 492
View: 6680
Book Description: 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.
Publisher: John Wiley & Sons
ISBN: 3527607749
Size: 44.70 MB
Format: PDF, Mobi
Category : Science
Languages : en
Pages : 492
View: 6680
Book Description: 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.
Molekulare Zellbiologie
Author: Harvey Lodish
Publisher: Walter de Gruyter
ISBN: 9783110144604
Size: 32.33 MB
Format: PDF, ePub
Category : Cell adhesion
Languages : de
Pages : 1448
View: 4852
Book Description:
Publisher: Walter de Gruyter
ISBN: 9783110144604
Size: 32.33 MB
Format: PDF, ePub
Category : Cell adhesion
Languages : de
Pages : 1448
View: 4852
Book Description:
Structure Function And Modulation Of Neuronal Voltage Gated Ion Channels
Author: Valentin K. Gribkoff
Publisher: John Wiley & Sons
ISBN: 0470429895
Size: 24.80 MB
Format: PDF, ePub, Docs
Category : Science
Languages : en
Pages : 496
View: 3195
Book Description: 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.
Publisher: John Wiley & Sons
ISBN: 0470429895
Size: 24.80 MB
Format: PDF, ePub, Docs
Category : Science
Languages : en
Pages : 496
View: 3195
Book Description: 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.
Handbook Of Receptors And Channels
Author: R. Alan North
Publisher: CRC Press
ISBN: 9780849383229
Size: 80.54 MB
Format: PDF, Kindle
Category : Science
Languages : en
Pages : 368
View: 5765
Book Description: This authoritative and comprehensive volume presents a perspective in the molecular and cellular diversity of membrane ion channels. Written in an accessible format, it depicts the structure and function of each of the known classes of ion channels. Each chapter provides amino acid sequences, including data base accession numbers; views of secondary, tertiary and quaternary channel structure; and evolutionary relationships among channels.
Publisher: CRC Press
ISBN: 9780849383229
Size: 80.54 MB
Format: PDF, Kindle
Category : Science
Languages : en
Pages : 368
View: 5765
Book Description: This authoritative and comprehensive volume presents a perspective in the molecular and cellular diversity of membrane ion channels. Written in an accessible format, it depicts the structure and function of each of the known classes of ion channels. Each chapter provides amino acid sequences, including data base accession numbers; views of secondary, tertiary and quaternary channel structure; and evolutionary relationships among channels.
Towards Voltage Gated Ion Channels Molecular Diodes
Author: Xin Zhou
Publisher:
ISBN:
Size: 48.54 MB
Format: PDF
Category :
Languages : en
Pages :
View: 360
Book Description: The goals of this project were to synthesize voltage-gated ion channels based upon previously studied pore-formers and to further explore the mechanism of ion transport with this type of pore-former. The syntheses of bis-macrocyclic bola-amphiphiles started with two different macrocycles prepared via a two-step cyclization from maleic anhydride by reaction with 1,8-octanediol alone or with triethyleneglycol. The macrocycles were then modified to a set of mono-adducts and bis-adducts by Michael addition of thiols (3-mercaptopropanol, 2-mercaptoacetic acid, or 3-mercaptopropionic acid). The mercaptopropanol adduct was converted to a mesylate and coupled with a carboxylate derivative to form a bis-macrocycle. Repetitious gel permeation chromatography gave a bis-macrocycle bearing only one head group, a carboxylate. The second head group was added via Michael addition to give a bis-macrocyclic bola-amphiphile which could have either the same head groups or different head groups. Two symmetrical transporters were synthesized via another route: two macrocycles reacted with 2-mercaptoethyl sulfide to generate a bis-macrocycle, and the same head group was then simultaneously added to both ends to give a symmetrical bola-amphiphile. Transporters with different combinations of head groups were synthesized to compare head group effects on cation transport properties, while different macrocycles were used in the backbone of transporter candidates to give two series of compounds for comparison of their behaviors. The second phase of this project investigated the transport properties of candidates using pH-stat titration. The pH-stat titration of bilayer vesicles allowed determination of dynamic transport properties: transport rate, apparent kinetic order and cation selectivity. Combined with information from planar bilayer experiments (done by D. Loock), it was found that an asymmetrical bis-macrocyclic bola-amphiphile with an acetate and a succinate head group behaves as voltage-gated ion channel in planar bilayers. An ion transport mechanism of the present system was proposed which involves the formation of active aggregates (probably dimers or oligomers).
Publisher:
ISBN:
Size: 48.54 MB
Format: PDF
Category :
Languages : en
Pages :
View: 360
Book Description: The goals of this project were to synthesize voltage-gated ion channels based upon previously studied pore-formers and to further explore the mechanism of ion transport with this type of pore-former. The syntheses of bis-macrocyclic bola-amphiphiles started with two different macrocycles prepared via a two-step cyclization from maleic anhydride by reaction with 1,8-octanediol alone or with triethyleneglycol. The macrocycles were then modified to a set of mono-adducts and bis-adducts by Michael addition of thiols (3-mercaptopropanol, 2-mercaptoacetic acid, or 3-mercaptopropionic acid). The mercaptopropanol adduct was converted to a mesylate and coupled with a carboxylate derivative to form a bis-macrocycle. Repetitious gel permeation chromatography gave a bis-macrocycle bearing only one head group, a carboxylate. The second head group was added via Michael addition to give a bis-macrocyclic bola-amphiphile which could have either the same head groups or different head groups. Two symmetrical transporters were synthesized via another route: two macrocycles reacted with 2-mercaptoethyl sulfide to generate a bis-macrocycle, and the same head group was then simultaneously added to both ends to give a symmetrical bola-amphiphile. Transporters with different combinations of head groups were synthesized to compare head group effects on cation transport properties, while different macrocycles were used in the backbone of transporter candidates to give two series of compounds for comparison of their behaviors. The second phase of this project investigated the transport properties of candidates using pH-stat titration. The pH-stat titration of bilayer vesicles allowed determination of dynamic transport properties: transport rate, apparent kinetic order and cation selectivity. Combined with information from planar bilayer experiments (done by D. Loock), it was found that an asymmetrical bis-macrocyclic bola-amphiphile with an acetate and a succinate head group behaves as voltage-gated ion channel in planar bilayers. An ion transport mechanism of the present system was proposed which involves the formation of active aggregates (probably dimers or oligomers).
Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels
Author: Malin Silverå Ejneby
Publisher: Linköping University Electronic Press
ISBN: 9176853187
Size: 24.63 MB
Format: PDF, ePub, Docs
Category :
Languages : en
Pages : 50
View: 3817
Book Description: 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.
Publisher: Linköping University Electronic Press
ISBN: 9176853187
Size: 24.63 MB
Format: PDF, ePub, Docs
Category :
Languages : en
Pages : 50
View: 3817
Book Description: 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.
Localization Of Voltage Gated Ion Channels In Mammalian Brain
Author: JS Trimmer
Publisher:
ISBN:
Size: 24.34 MB
Format: PDF, ePub, Mobi
Category :
Languages : en
Pages :
View: 4433
Book Description: The intrinsic electrical properties of neurons are shaped in large part by the action of voltage-gated ion channels. Molecular cloning studies have revealed a large family of ion channel genes, many of which are expressed in mammalian brain. Much recent effort has focused on determining the contribution of the protein products of these genes to neuronal function. This requires knowledge of the abundance and distribution of the constituent subunits of the channels in specific mammalian central neurons. Here we review progress made in recent studies aimed at localizing specific ion channel subunits using in situ hybridization and immunohistochemistry. We then discuss the implications of these results in terms of neuronal physiology and neuronal mechanisms underlying the observed patterns of expression. Copyright © 2004 by Annual Reviews. All rights reserved.
Publisher:
ISBN:
Size: 24.34 MB
Format: PDF, ePub, Mobi
Category :
Languages : en
Pages :
View: 4433
Book Description: The intrinsic electrical properties of neurons are shaped in large part by the action of voltage-gated ion channels. Molecular cloning studies have revealed a large family of ion channel genes, many of which are expressed in mammalian brain. Much recent effort has focused on determining the contribution of the protein products of these genes to neuronal function. This requires knowledge of the abundance and distribution of the constituent subunits of the channels in specific mammalian central neurons. Here we review progress made in recent studies aimed at localizing specific ion channel subunits using in situ hybridization and immunohistochemistry. We then discuss the implications of these results in terms of neuronal physiology and neuronal mechanisms underlying the observed patterns of expression. Copyright © 2004 by Annual Reviews. All rights reserved.
Understanding Voltage Gated Ion Channels Via Molecular Archeology
Author: Tsai-Tien Tseng
Publisher:
ISBN:
Size: 48.70 MB
Format: PDF, ePub, Docs
Category :
Languages : en
Pages : 518
View: 4152
Book Description:
Publisher:
ISBN:
Size: 48.70 MB
Format: PDF, ePub, Docs
Category :
Languages : en
Pages : 518
View: 4152
Book Description:
An Optical Approach To Structure Function Relationships In Voltage Gated Ion Channels
Author: Osei Kwame Asamoah
Publisher:
ISBN:
Size: 21.31 MB
Format: PDF, ePub, Mobi
Category :
Languages : en
Pages : 310
View: 6485
Book Description:
Publisher:
ISBN:
Size: 21.31 MB
Format: PDF, ePub, Mobi
Category :
Languages : en
Pages : 310
View: 6485
Book Description:
