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Unsaturated Free Fatty Acids Increase Benzodiazepine Receptor Agonist Binding Depending on the Subunit Composition of the GABAA Receptor Complex

Abstract: It has been shown previously that unsaturated free fatty acids (FFAs) strongly enhance the binding of agonist benzodiazepine receptor ligands and GABAA receptor ligands in the CNS in vitro. To investigate the selectivity of this effect, recombinant human GABAA/benzodiazepine receptor complexes formed by different subunit compositions (αxβyγ2, x = 1, 2, 3, and 5; y = 1, 2, and 3) were expressed using the baculovirus‐transfected Sf9 insect cell system. At 10−4M, unsaturated FFAs, particularly arachidonic (20:4) and docosahexaenoic (22:6) acids, strongly stimulated (>200% of control values) the binding of [3H]flunitrazepam ([3H]FNM) to the α3β2γ2 receptor combination in whole cell preparations. No effect or small increases in levels of unsaturated FFAs on [3H]FNM binding to α1βxγ2 and α2βxγ2 receptor combinations were observed, and weak effects (130% of control values) were detected using the α5β2γ2 receptor combination. The saturated FFAs, stearic and palmitic acids, were without effect on [3H]FNM binding to any combination of receptor complexes. The hydroxylated unsaturated FFAs, ricinoleic and ricinelaidic acids, were shown to decrease the binding of [3H]FNM only if an α1β2γ2 receptor combination was used. Given the heterogeneity of the GABAA/benzodiazepine receptor subunit distribution in the CNS, the effects of FFAs on the benzodiazepine receptor can be assumed to vary at both cellular and regional levels.