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Voltage Sensitive Ion Channels

Voltage Sensitive Ion Channels PDF
Author: H. Richard Leuchtag
Publisher: Springer Science & Business Media
Release: 2008-12-21
Size: 65.72 MB
Format: PDF, Mobi
Category : Science
Languages : en
Pages : 532
View: 5745

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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.

Site And Mechanism Of Action Of Resin Acids On Voltage Gated Ion Channels

Site and Mechanism of Action of Resin Acids on Voltage Gated Ion Channels PDF
Author: Malin Silverå Ejneby
Publisher: Linköping University Electronic Press
Release: 2018-05-15
Size: 35.72 MB
Format: PDF, ePub, Docs
Category :
Languages : en
Pages : 50
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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.

Molecules To Models

Molecules to Models PDF
Author: Katrina L. Kelner
Publisher: Amer Assn for the Advancement of
Release: 1989
Size: 44.34 MB
Format: PDF, ePub, Mobi
Category : Neurobiology.
Languages : en
Pages : 456
View: 3109

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Molecular Action Of Insecticides On Ion Channels

Molecular Action of Insecticides on Ion Channels PDF
Author: John Marshall Clark
Publisher: Amer Chemical Society
Release: 1995
Size: 14.15 MB
Format: PDF, Docs
Category : Science
Languages : en
Pages : 356
View: 2355

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Documents ongoing research into the molecular understanding of insecticide action, including the action of insecticides on major ion channel families, voltage-sensitive channels, ligand-gated channels, and biopesticide-induced channels. Presents recent advances in how researchers envision molecular binding sites of insecticides on ion channels and the molecular alterations of these sites resulting in site-insensitive resistance mechanisms. Describes new receptor-ion channels and mosaic receptor organizations as novel sites of insecticide action.

Cardiac Morphogenesis

Cardiac Morphogenesis PDF
Author: Victor J. Ferrans
Publisher: Elsevier Publishing Company
Release: 1985
Size: 51.31 MB
Format: PDF, ePub, Docs
Category : Heart
Languages : en
Pages : 282
View: 5618

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