INHIBITION OF THE KV4 (SHAL) FAMILY OF TRANSIENT K-ACID( CURRENTS BY ARACHIDONIC)

We have found that transient A-type currents expressed in Xenopus oocy tes 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 S haker currents showed a modest increase in peak amplitude. The inhibit ion of Kv4 channels was not prevented by cyclo-oxygenase, lipoxygenase , or cytochrome P-450 inhibitors and was mimicked by 5,8,11,14-eicosat etraynoic acid, an arachidonic acid analog that is not metabolized by these pathways. Other unsaturated cis fatty acids with more than two d ouble 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 conce ntrations 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 th e N terminal is not required for arachidonic acid action but that the S4-S5 loop may influence the effect.