Abstract
Endogenous neurosteroids and synthetic neuroactive steroid analogs are among the most potent and efficacious potentiators of the mammalian GABA-A receptor. The compounds interact with one or more sites on the receptor leading to an increase in the channel open probability through a set of changes in the open and closed time distributions. The endogenous neurosteroid allopregnanolone potentiates the α1β2γ2L GABA-A receptor by enhancing the mean duration and prevalence of the longest-lived open time component and by reducing the prevalence of the longest-lived intracluster closed time component. Thus the channel mean open time is increased and the mean closed time duration is decreased, resulting in potentiation of channel function. Some of the other previously characterized neurosteroids and steroid analogs act through similar mechanisms while others affect a subset of these parameters. The steroids modulate the GABA-A receptor through interactions with the membrane-spanning region of the receptor. However, the number of binding sites that mediate the actions of steroids is unclear. We discuss data supporting the notions of a single site vs. multiple sites mediating the potentiating actions of steroids.
Highlights
Neurosteroids are synthesized in the central and peripheral nervous system from cholesterol or other steroidal precursors [9, 14, 31]
From a viewpoint of medicinal chemistry, the steroid ring structure serves as a useful pharmacophore template to create synthetic neuroactive steroid analogs
By employing single-channel patch clamp recordings we showed that receptors in cells pretreated with a neuroactive steroid that was subsequently removed from the bath remained potentiated for long periods of time
Summary
Neurosteroids are synthesized in the central and peripheral nervous system from cholesterol or other steroidal precursors [9, 14, 31]. We reasoned that if a single site mediates all actions of the two steroids the presence of etiocholanolone, a steroid with a single kinetic effect, would reduce the ability of pregnanolone to elicit a change in the mean duration of OT3 and the prevalence of CT3. The effect of pregnanolone on the mean duration of OT3 and the prevalence of CT3 is unchanged in the presence of etiocholanolone These findings are most consistent with the concept of multiple, non-overlapping steroid binding sites mediating receptor potentiation [24]. In the model of multiple binding sites mediating steroid effects on the GABA-A receptor, these findings suggest that ethanol selectively modulates the interaction of allopregnanolone with the site that mediates the increase in the mean duration of long openings. The data indicate that steroid interactions with a single α subunit can lead to changes in the open and closed time distributions and mediate potentiation by neuroactive steroids
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