Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid.
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 mM 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.
Villarroel
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Department of Molecular and Cellular Physiology, Beckman Center, Stanford University, California 94305, USA.
Schwarz
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D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D003001:Cloning, Molecular; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D005227:Fatty Acids / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008560:Membrane Fluidity / Q000187:drug effects; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051637:Shaker Superfamily of Potassium Channels; D051672:Shal Potassium Channels; D014982:Xenopus laevis
D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D005227:Fatty Acids; D016859:Lipoxygenase Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; D051637:Shaker Superfamily of Potassium Channels; D051672:Shal Potassium Channels; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D011188:Potassium