Slow Actions of Neuroactive Steroids at GABA_AReceptors

Abstract

Neuroactive steroids are potent and efficacious modulators of GABA A receptor activity and are potent sedatives and anesthetics. These positive modulators of GABA A receptors both potentiate the actions of GABA at the receptor and, at higher concentrations, directly gate the channel. The contribution of direct gating to the cellular and behavioral effects of neuroactive steroids is considered of little significance because it has been generally found that concentrations well above those needed for anesthesia are required to gate channels. By studying solitary glutamatergic neurons devoid of synaptic GABA input, we show that direct gating occurs and significantly alters membrane excitability at concentrations Յ100 nM. We propose that the relevance of direct gating has been overlooked partly because of the extremely slow kinetics of receptor activation and deactivation. We show that slow deactivation of directly gated currents does not result from an inherently tight ligand-receptor interaction because the slow deactivation is markedly accelerated by ␥-cyclodextrin application. We hypothesize that steroids access the relevant GABA A receptor site from a non-aqueous reservoir, likely the plasma membrane, and that it is slow reservoir accumulation and departure that accounts for the slow kinetics of receptor gating by neuroactive steroids.

Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor

“…These compounds are thought to partition and accumulate into the plasma membrane from where they access a binding site on the receptor. The rate-limiting factor for deactivation may then be reservoir emptying rather than the intrinsic kinetics of ligand dissociation (33). We propose that similar mechanisms may underlie some of the distinctive effects of levamisole on L-AChRs.…”

Mechanisms of neurosteroid interactions with GABAA receptors

“…Like many GABA-receptor potentiators, including barbiturates, etomidate, and propofol, neuroactive steroids augment the whole-cell response to low concentrations of GABA (Callachan et al, 1987;Cottrell et al, 1987;Majewska et al, 1986;Shu et al, 2004). Depending on subunit composition of the receptor and agonist, another important effect of steroids is to increase the efficacy of agonist actions (Bianchi & Macdonald, 2003;Maksay et al, 2000;Wohlfarth et al, 2002).…”

“…Direct gating by steroids is inefficient, with maximum responses well below responses generated by saturating GABA (Shu et al, 2004). Nevertheless, even small currents resulting from direct gating can have a significant impact on cellular excitability (Shu et al, 2004).…”

“…Nevertheless, even small currents resulting from direct gating can have a significant impact on cellular excitability (Shu et al, 2004). Furthermore, we recently reported that the kinetics of onset and offset of direct gating are particularly slow.…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…This circumstance minimizes the possibility that a direct activation of GABA A receptor function by neurosteroids is responsible for the neurosteroid contribution to the GABAmimetic profile of ethanol. However, given the recent report consistent with a direct effect of neurosteroids on GABA A receptor gating (Shu et al, 2004), some caution must be taken with this interpretation.…”