Eur J Pharmacol 2008 May 31;5861-3:67-73. doi: 10.1016/j.ejphar.2008.02.063.

Neurosteroids 3beta, 20 (R/S)-pregnandiols decrease offset rate of the GABA-site activation at the recombinant GABA A receptor.

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Neurosteroids directly modulate ligand gated ion channels such as GABA A receptors. Two such molecules, 3beta-OH A-ring reduced pregnane steroids and pregnenolone sulfate (PS), inhibit recombinant GABA A receptor. Using a two-electrode voltage-clamp technique, we compared the effect of 5alpha-pregnan-3beta,20(S)-diol (UC1019), 5beta-pregnan-3beta, 20(R)-diol (UC1020) and PS on the activation onset and offset times of the recombinant GABA A receptor (rat alpha1beta2gamma2L) in Xenopus oocytes. Rapid solution changes allowed the kinetic analysis of GABA-evoked currents. Steroids were co-applied with 30 microM GABA for 10 s, followed by a 80 s washout period. PS (> ir =0.3 microM) moderately increased the slow onset rate (k(on-S)) of GABA-response. PS had no significant effects on the fast onset rate (k(on-F)). UC1019 and UC1020 decreased the k(on-S) of the GABA-response in a concentration-dependent manner with no significant effects on the k(on-F). Like PS, UC1019 and UC1020 decreased the slow offset rates (k(off-S)). In addition, PS increased the fast offset rate (k(off-F)) in a concentration-dependent manner, while UC1019 and UC1020 decreased k(off-F). The EC50 of PS to increase k(off-F) was calculated as 0.47+/-0.1 microM. The corresponding IC50 values of UC1019 and UC1020 to decrease k(off-F) were 5.0+/-0.5 microM and 8.4+/-0.9 microM, respectively. These results suggest differential actions of PS and 3beta, 20(R/S)-pregnandiols on the offset time course of GABA-site activation.

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