Open AccessModulation of KCa3.1 Channels by Eicosanoids, Omega-3 Fatty Acids, and Molecular Determinants
Author(s) -
Michael Kacik,
Aida Oliván-Viguera,
Ralf Köhler
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0112081
Subject(s) - chemistry , stereochemistry , biochemistry , patch clamp , biophysics , biology , receptor
Background Cytochrome P450- and ω-hydrolase products (epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraeonic acid (20-HETE)), natural omega-3 fatty acids (ω3), and pentacyclic triterpenes have been proposed to contribute to a wide range of vaso-protective and anti-fibrotic/anti-cancer signaling pathways including the modula-tion of membrane ion channels. Here we studied the modulation of intermediate-conductance Ca 2+ /calmodulin-regulated K + channels (K Ca 3.1) by EETs, 20-HETE, ω3, and pentacyclic triterpenes and the structural requirements of these fatty acids to exert channel blockade. Methodology/Principal Findings We studied modulation of cloned human hK Ca 3.1 and the mutant hK Ca 3.1 V275A in HEK-293 cells, of rK Ca 3.1 in aortic endothelial cells, and of mK Ca 3.1 in 3T3-fibroblasts by inside-out and whole-cell patch-clamp experiments, respectively. In inside-out patches, Ca 2+ -activated hK Ca 3.1 were inhibited by the ω3, DHA and α-LA, and the ω6, AA, in the lower µmolar range and with similar potencies. 5,6-EET, 8,9-EET, 5,6-DiHETE, and saturated arachidic acid, had no appreciable effects. In contrast, 14,15-EET, its stable derivative, 14,15-EEZE, and 20-HETE produced channel inhibition. 11,12-EET displayed less inhibitory activity. The K Ca 3.1 V275A mutant channel was insensitive to any of the blocking EETs. Non-blocking 5,6-EET antagonized the inhibition caused by AA and augmented cloned hK Ca 3.1 and rK Ca 3.1 whole-cell currents. Pentacyclic triterpenes did not modulate K Ca 3.1 currents. Conclusions/Significance Inhibition of K Ca 3.1 by EETs (14,15-EET), 20-HETE, and ω3 critically depended on the presence of electron double bonds and hydrophobicity within the 10 carbons preceding the carboxyl-head of the molecules. From the physiological perspective, metabolism of AA to non-blocking 5,6,- and 8,9-EET may cause AA-de-blockade and contribute to cellular signal transduction processes influenced by these fatty acids.