J Biol Chem, Vol. 273, Issue 18, 11056-11061, May 1, 1998

Functional Modulation of Human Recombinant -Aminobutyric Acid Type A Receptor by Docosahexaenoic Acid

Junichi Nabekura, Kazuo Noguchi, Michael-Robin Witt^¶, Mogens Nielsen^¶, and Norio Akaike

From the  Department of Physiology, Faculty of Medicine, Kyushu University 3-1-1 Maidashi Higashi-ku Fukuoka, 812-82, Japan and the ^¶  Research Institute of Biological Psychiatry, St. Hans Hospital, DK-4000 Roskilde, Denmark

Human -aminobutyric acid type A (GABA_A) receptors were expressed in the baculovirus/Sf-9 insect cell expression system using recombinant cDNA of _122s subunits. The effect of unsaturated fatty acids on GABA_A receptor complexes was investigated electrophysiologically using conventional whole cell recording under voltage clamp. Three distinct effects of docosahexaenoic acid (DHA) on the GABA responses were observed. First, DHA, at a concentration of 10⁷ M or greater, accelerated the desensitization after the peak of the GABA-induced current. Second, DHA (10⁶ M) potentiated the peak amplitude of GABA response. This potentiation by DHA was inhibited in the presence of Zn²⁺ (10⁵ M); Cu²⁺ and Ni²⁺ mimicked the action of Zn²⁺. Zn²⁺ (10⁵ M) did not block the GABA response on _122s receptor complexes. Third, DHA, at a concentration of 3 × 10⁶ M or higher, gradually suppressed the peak amplitude of GABA response. A protein kinase A inhibitor, a protein kinase C inhibitor, and a Ca²⁺ chelator did not modify the effects of DHA on GABA-induced chloride ion current. Six unsaturated fatty acids other than DHA were examined. Arachidonic acid mimicked the effect of DHA while e.g. oleic acid had no effect.

The inhibition of the GABA response in the presence of DHA was also observed in cells expressing GABA_A receptors of ₁ and ₂ subunit combinations. The data show that the  subunit is essential for DHA and arachidonic acid to potentiate the GABA-induced Cl channel activity and to affect the desensitization kinetics of the GABA_A receptor.