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Journal of Neuroscience, Vol 16, 2522-2532, Copyright © 1996 by Society for Neuroscience
Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid
A Villarroel and TL Schwarz
Department of Molecular and Cellular Physiology, Beckman Center, Stanford University, California 94305, USA.
We have found that transient A-type currents expressed in Xenopus oocytes
from members of the Kv4 family are suppressed by arachidonic acid. Currents
from members of the Kv1, Kv2, and Kv3 families showed little or no
inhibition by fatty acids in this expression system, although Shaker
currents showed a modest increase in peak amplitude. The inhibition of Kv4
channels was not prevented by cyclo-oxygenase, lipoxygenase, or cytochrome
P-450 inhibitors and was mimicked by 5,8,11,14-eicosatetraynoic acid, an
arachidonic acid analog that is not metabolized by these pathways. Other
unsaturated cis fatty acids with more than two double bonds produced a
similar effect. In inside-out macropatches, the current was reversibly
reduced >50% by 2 microM arachidonic acid, and the inhibition developed
in <40 sec. These results suggest that, at concentrations that are
likely to be physiologically relevant, arachidonic acid interacts directly
with the channel or with a closely associated component. Preliminary
mutagenesis of Kv4.2 channels indicates that the N terminal is not required
for arachidonic acid action but that the S4-S5 loop may influence the
effect.
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