Document Detail


RNA editing modulates the binding of drugs and highly unsaturated fatty acids to the open pore of Kv potassium channels.
MedLine Citation:
PMID:  20461057     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The time course of inactivation of voltage-activated potassium (Kv) channels is an important determinant of the firing rate of neurons. In many Kv channels highly unsaturated lipids as arachidonic acid, docosahexaenoic acid and anandamide can induce fast inactivation. We found that these lipids interact with hydrophobic residues lining the inner cavity of the pore. We analysed the effects of these lipids on Kv1.1 current kinetics and their competition with intracellular tetraethylammonium and Kvbeta subunits. Our data suggest that inactivation most likely represents occlusion of the permeation pathway, similar to drugs that produce 'open-channel block'. Open-channel block by drugs and lipids was strongly reduced in Kv1.1 channels whose amino acid sequence was altered by RNA editing in the pore cavity, and in Kv1.x heteromeric channels containing edited Kv1.1 subunits. We show that differential editing of Kv1.1 channels in different regions of the brain can profoundly alter the pharmacology of Kv1.x channels. Our findings provide a mechanistic understanding of lipid-induced inactivation and establish RNA editing as a mechanism to induce drug and lipid resistance in Kv channels.
Authors:
Niels Decher; Anne K Streit; Markus Rapedius; Michael F Netter; Stefanie Marzian; Petra Ehling; Günter Schlichthörl; Tobias Craan; Vijay Renigunta; Annemarie Köhler; Richard C Dodel; Ricardo A Navarro-Polanco; Regina Preisig-Müller; Gerhard Klebe; Thomas Budde; Thomas Baukrowitz; Jürgen Daut
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-11
Journal Detail:
Title:  The EMBO journal     Volume:  29     ISSN:  1460-2075     ISO Abbreviation:  EMBO J.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-07     Completed Date:  2010-08-05     Revised Date:  2011-08-01    
Medline Journal Info:
Nlm Unique ID:  8208664     Medline TA:  EMBO J     Country:  England    
Other Details:
Languages:  eng     Pagination:  2101-13     Citation Subset:  IM    
Affiliation:
Institut für Physiologie und Pathophysiologie, Universität Marburg, Marburg, Germany. decher@staff.uni-marburg.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Arachidonic Acid / metabolism
Binding Sites
Fatty Acids, Unsaturated / metabolism*
Humans
Models, Molecular
Mutation
Neurons / drug effects,  metabolism
Oocytes / drug effects,  metabolism
Potassium Channels, Voltage-Gated / antagonists & inhibitors*,  genetics,  metabolism*
Protein Binding
RNA Editing*
Rats
Tetraethylammonium / pharmacology*
Xenopus laevis
Chemical
Reg. No./Substance:
0/Fatty Acids, Unsaturated; 0/Potassium Channels, Voltage-Gated; 506-32-1/Arachidonic Acid; 66-40-0/Tetraethylammonium
Comments/Corrections
Comment In:
EMBO J. 2010 Jul 7;29(13):2097-8   [PMID:  20606701 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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