title: RNA editing modulates the binding of drugs and highly unsaturated fatty acids to the open pore of Kv potassium channels.
abstract: 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.affiliation: Institut für Physiologie und Pathophysiologie, Universität Marburg, Marburg, Germany. decher@staff.uni-marburg.de
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.forename: Anne K
authors.initials: AK
authors.lastname: Streit
authors.forename: Markus
authors.initials: M
authors.lastname: Rapedius
authors.forename: Michael F
authors.initials: MF
authors.lastname: Netter
authors.forename: Stefanie
authors.initials: S
authors.lastname: Marzian
authors.forename: Petra
authors.initials: P
authors.lastname: Ehling
authors.forename: Günter
authors.initials: G
authors.lastname: Schlichthörl
authors.forename: Tobias
authors.initials: T
authors.lastname: Craan
authors.forename: Vijay
authors.initials: V
authors.lastname: Renigunta
authors.forename: Annemarie
authors.initials: A
authors.lastname: Köhler
authors.forename: Richard C
authors.initials: RC
authors.lastname: Dodel
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Navarro-Polanco
authors.forename: Regina
authors.initials: R
authors.lastname: Preisig-Müller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Daut
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001665:Binding Sites; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017393:RNA Editing; D051381:Rats; D019789:Tetraethylammonium / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D005231:Fatty Acids, Unsaturated; D024642:Potassium Channels, Voltage-Gated; D016718:Arachidonic Acid; D019789:Tetraethylammonium
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