The influence of the subunit composition of human GABA A receptors upon the GABA-modulatory properties of 5α-pregnan-3α-ol-20-one (5α,3α) has been examined using the Xenopus laevis oocyte expression system and the two electrode voltage-clamp technique. Steroid potency (EC 50 ) is modestly influenced by the α-isoform (α x β 1 γ 2L ; x =1–6). α 2 -, α 4 - and α 5 -containing receptors are significantly less sensitive to the action of low concentrations of 5α,3α (10–100 nM) when compared to α 1,3,6 β 1 γ 2L receptors. Additionally, the maximal effect of the steroid is favoured at α 6 -containing receptors. The β-isoform (α 1 β y γ 2L ; y =1–3) has little influence on the GABA-modulatory effect of the neurosteroid. The EC 50 of 5α,3α is only modestly influenced by the omission of the γ 2 subunit (α 1 β 1 γ 2L vs α 1 β 1 ): while the maximal effect is favoured by the binary complex. However, the identity of the γ subunit influences the GABA A -modulatory potency of 5α,3α with γ 2 - and γ 1 -containing receptors being the most and the least sensitive to 5α,3α, respectively. Finally, incorporation of the ε, or δ subunit dramatically reduces and augments the GABA-enhancing actions of the steroid, respectively. These findings provide evidence that 5α,3α discriminates amongst recombinant receptors of varied subunit composition. Furthermore, this selectivity may contribute to their neuronal specificity and behavioural profile.
Neuropharmacology – Elsevier
Published: Sep 1, 2002
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