Fig. (1).
Structure and actions of neurosteroids. Allopregnanolone (3α5α-P; top left) is an endogenous PAM neurosteroid characterized by a 3α-hydroxyl group. Its epimer, epi-allopregnanolone (3β5α-P; top right), is a NAM neurosteroid characterized by a 3β-hydroxyl group. The lower panels show simulated electrophysiological tracings of GABAA-receptor currents constructed using a three-state (resting-active-desensitized) Monod-Wyman-Changeux model (simulation performed in ChanneLab™ ver. 2 software provided by Stephen F. Traynelis, Emory University School of Medicine). At low open probability (PA), (left lower panel) 3α5α-P significantly potentiates the channel activation elicited by a low concentration of the orthosteric agonist GABA, whereas 3β5α-P (not shown) has no effect. In contrast, at high PA (such as that produced by a saturating concentration of GABA) 3α5α-P weakly (lower middle panel) and 3β5α-P substantially desensitize the receptor, thus inhibiting the steady-state current.