FUNCTIONAL MODULATION OF HUMAN RECOMBINANT GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR BY DOCOSAHEXAENOIC ACID

Human gamma-aminobutyric acid type A (GABA(A)) receptors were expresse d in the baculovirus/Sf-9 insect cell expression system using recombin ant cDNA of alpha(1) beta(2) gamma(2s) subunits. The effect of unsatur ated fatty acids on GABA(A) receptor complexes was investigated electr ophysiologically using conventional whole cell recording under voltage clamp. Three distinct effects of docosahexaenoic acid (DHA) on the GA BA responses were observed, First, DHA, at a concentration of 10(-7) a r or greater, accelerated the desensitization after the peak of the GA BA-induced current Second, DHA (10(-6) M) potentiated the peak amplitu de of GABA response. This potentiation by DHA was inhibited in the pre sence of Zn2+ (10(-5) M); Cu2+ and Ni2+ mimicked the action of Zn2+. Z n2+ (10(-5) M) did not block the GABA response on alpha(1) beta(2) gam ma(2s) receptor complexes. Third, DHA, at a concentration of 3 x 10(-6 ) M or higher, gradually suppressed the peak amplitude of GABA respons e. A protein kinase A inhibitor, a protein kinase C inhibitor, and a C a2+ chelator did not modify the effects of DHA on GABA-induced chlorid e ion current, Six unsaturated fatty acids other than DHA were examine d. Arachidonic acid mimicked the effect of DHA while e.g. oleic acid h ad no effect, The inhibition of the GABA response in the presence of D HA was also observed in cells expressing GABAA receptors of alpha(1) a nd beta(2) subunit combinations. The data show that the gamma subunit is essential for DHA and arachidonic acid to potentiate the GABA-induc ed Cl- channel activity and to affect the desensitization kinetics of the GABA(A) receptor.