Herein we demonstrate that the major metabolites of ethanol in neural tissues, fatty acid ethyl esters, dramatically accelerate the kinetics of the voltage-induced activation of the human brain delayed rectifier potassium channel, Kv1.1. Specifically, the external application of ethyl oleate (20 M) to Sf9 cells expressing the recombinant Kv1.1 channel resulted in a decrease in the rise times of the macroscopic current (e.g. from 51.7 ؎ 13.1 to 12.8 ؎ 3.0 ms at 0 mV for 10 -90% rise times) and a 10-mV hyperpolarizing shift (at 0 mV) in the voltage dependence of channel activation. These effects were dose-dependent (half-maximal effect at 7 M), saturable and specific (i.e. fatty acid methyl esters were without effect). Although application of either ethanol or oleic acid alone did not result in alterations of the activation kinetics, the concomitant application of ethanol and oleic acid reproduced the effects of fatty acid ethyl esters with a temporal course which paralleled the intracellular accumulation of fatty acid ethyl esters in Sf9 cells. Moreover, application of fatty acid ethyl esters (but not ethanol) to rat hippocampal cells in culture produced similar effects on hippocampal delayed rectifier currents. Collectively, these results demonstrate that pathophysiologically relevant concentrations of metabolites of ethanol, fatty acid ethyl esters, modulate the function of a prototypic neuronal ion channel and thus likely contribute to the pathophysiologic sequelae of ethanol abuse in excitable tissues.Elucidation of the biochemical mechanisms underlying the effects of ethanol in electrically excitable tissues has been a long standing goal in neurochemistry (e.g. Refs. 1-3). Due to the structural simplicity of ethanol, the difficulties in identifying the precise biochemical mechanisms responsible for ethanol-induced alterations in electrophysiologic function have represented a fundamental paradox in neuropharmacology. Although multiple effects of ethanol on ion channel function have been demonstrated, consistent alterations in ion channel properties at pathophysiologically relevant concentrations of ethanol (i.e. 0.01-0.1% (2-20 mM)) have not been forthcoming (4 -7). The discordance between the amounts of ethanol necessary to modulate ion channel function in isolated cells and that necessary for perturbation of electrophysiologic function in intact neural structures represents an unresolved and highly controversial issue in the pathobiology of alcohol.Fatty acid ethyl esters are the major nonoxidative metabolite of ethanol in humans and represent the predominant ethanol metabolite in human brain after alcohol ingestion (8 -10). Moreover, detailed examination of fatty acid ethyl ester synthesis in distinct anatomic loci in brain has demonstrated a high correlation between ethanol-induced pathology and the metabolic rates of fatty acid ethyl ester production (11). Since recent studies have identified the electrophysiologic effects of nonesterified fatty acids on ion channels (12-17), we hypothesized that some of...