TIME-DEPENDENT AND VOLTAGE-DEPENDENT BLOCK OF DELAYED RECTIFIER POTASSIUM CHANNELS BY DOCOSAHEXAENOIC ACID

Docosahexaenoic acid (22:6n3) acts at an extracellular site to produce a voltage- and time-dependent block of the delayed rectifier current (I-K) similar to that classically described for intracellularly applie d quaternary ammonia compounds. In dissociated cells from the pineal g land, some long-chain polyunsaturated fatty acids reduced both late su stained (I-K) (for 22:6n3, IC50 = 2.5 +/- 0.3 mu M) and early transien t (I-A) (IC50 = 2.0 +/- 0.1 mu M) components of potassium current when applied extracellularly, whereas the monounsaturate oleic acid had mi nimal efficacy, From comparisons of other related fatty acids, it was determined that there is a structural requirement for polyunsaturation to block I-K. In contrast, chain-elongated 22-carbon polyunsaturates acted similarly to their precursor 20-carbon fatty acids (arachidonic acid and eicosapentanoic acid), Block of I-K by 22:6n3 was accompanied by a dose-dependent acceleration of the current decay in both whole-c ell and outside-out membrane patches, and 22:6n3 increased the macrosc opic inactivation rate of I-A. The combined ''eicosanoid'' inhibitor e icosatetraenoic acid, when included in the patch pipette, did not anta gonize the action of 22:6n3. Instead, eicosatetraenoic acid produced a direct block of I-K when applied extracellularly at high concentratio ns (25 mu M). Analyses of voltage- and time-dependent block by 22:6n3 support the hypothesis that certain fatty acids directly interact with and preferentially block the open state of some potassium channels. W e also describe an interaction between fatty acid block and zinc; 22:6 n3 failed to block either I-A or I-K in the presence of zinc or cadmiu m, whereas extracellular calcium did not affect the response. These st udies suggest a possible biological function for 22:6n3 in the nervous system, which may underlie its essential role during neural developme nt.