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(Received for publication, September 10, 1996, and in revised form, October 10, 1996)
From the Division of Bioorganic Chemistry and Molecular
Pharmacology, Washington University School of Medicine, St.
Louis, Missouri 63110
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 µM) 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 µM), 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.
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