Opposing effects of different steroid sulfates on GABAA receptor-mediated chloride uptake

Steroids with the 3alpha-hydroxy-5alpha- or 5beta-reduced configurations of the A ring interact with the gamma-aminobutyric acid (GABA) type A receptor chloride channel complex and potentiate the stimulation of Cl- uptake by GABA agonists. Conversely, the sulfate esters of 3beta-hydroxy-5-ene neurosteroids pregnenolone and dehydroepiandrosterone behave as inhibitory modulators. In the present work, steroid sulfates were tested for their ability to modulate muscimol-induced chloride ion uptake into cortical synaptoneurosomes. 3alpha-Hydroxy-5alpha-pregnan-20-one sulfate and several other 3alpha-hydroxy-steroid sulfates potentiated, whereas 3beta-hydroxy-steroid sulfates inhibited muscimol effect. It is concluded that GABA-agonistic or antagonistic properties of steroid sulfates depend on the alpha or beta orientation of the sulfate moiety linked to the A ring.