THE EFFECT OF ARACHIDONIC-ACID AND FREE FATTY-ACIDS ON VESICULAR UPTAKE OF GLUTAMATE AND GAMMA-AMINOBUTYRIC-ACID

The manner in which arachidonic acid and other free fatty acids influe nce the vesicular uptake of glutamate and gamma-aminobutyric acid (GAB A) has been investigated. The cis-polyunsaturated fatty acid arachidon ic acid (20:4), eicosapentanoic acid (20:5) and linolenic acid (18:3) at 150 nmol/mg protein (50 mu M) inhibited the vesicular uptake of glu tamate and GABA more than 70%. Reduced inhibition of vesicular uptake was seen with the cis-monounsaturated fatty acid oleic acid (18:1) and the trans-mono-unsaturated fatty acid elaidic acid (18:1). The satura ted fatty acids stearic acid (16:0) and arachidic acid (20:0) had no s ignificant effect on the uptake. The inhibition of vesicular uptake by arachidonic acid was prevented by the addition of fatty acid free bov ine serum albumin. Arachidonic acid inhibited in a dose-dependent mann er the generation of the transmembrane pH gradient of the synaptic ves icles. This inhibition was proportional to the inhibition of the vesic ular uptake of glutamate and GABA. The saturated fatty acid arachidic acid showed no inhibition of Delta pH generation. Arachidonic acid at 200 nmol/mg of protein did not increase the uptake-independent leakage of glutamate and GABA from the vesicles, showing that the effect of a rachidonic acid is not caused by an unspecific detergent effect. These results suggest that arachidonic acid and other polyunsaturated fatty acids an acting like proton-ionophores on the vesicular uptake of the se neurotransmitters. This finding map have implications for the incre ased fatty acid concentration during pathological conditions like isch emia and in long term potentiation. (C) 1998 Elsevier Science B.V.