The sticky issue of neurosteroids and GABAA receptors

Abstract

Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABA A receptors. Thus, they are of physiological and clinical relevance for their ability to modulate inhibitory function in the central nervous system. Despite their importance, fundamental issues of neurosteroid actions remain unresolved. Recent evidence suggests that glutamatergic principal neurons, rather than glia, are major sources of neurosteroid synthesis. Other recent studies have identified putative neurosteroid binding sites on GABA A receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane domain binding sites within GABA A receptors. This has implications for the design of future neuroactive steroids, since the lipid solubility and related accessibility properties of the ligand may be key determinants of receptor modulation. OverviewEndogenous neurosteroids and their synthetic analogues (neuroactive steroids) are among the most potent and effective modulators of γ-aminobutyric acid-A (GABA A ) receptors known [1]. Although a role for neurosteroids as endogenous modulators has been postulated for nearly thirty years, fundamental issues of neurosteroid actions on circuits, cells, and receptors remain unresolved. For instance, which cells in the CNS synthesize neurosteroids? Once synthesized, how, where, and at what concentrations do these modulators reach their target receptors? Recent evidence suggests that principal neurons, rather than glia, may dominate CNS neurosteroid synthesis. Other studies have identified putative neurosteroid binding sites on GABA A receptors. Parallel pharmacological approaches have implied a non-classical interaction between neurosteroid ligands and GABA A receptors, involving a membrane route of access and a low-affinity receptor interaction for neurosteroids. Here, we discuss our opinion

GABAA receptor plasticity in Jurkat T cells

“…It is now well recognized that progesterone and its metabolites are potent allosteric modulators of GABA A R function through a direct, nongenomic interaction with specific receptor subtypes, being the dcontaining receptor especially sensitive to them [27]. However, fluctuations in the concentration of neuroactive steroids affect not only GABA A R function but also the expression of receptor subunits [6].…”

GABA Receptors: Pharmacological Potential and Pitfalls

“…The potentiating effect of neurosteroids can be mediated by steroid interactions with its site within the same β-α pair that mediates receptor activation as well as the opposite β-α pair [179]. Chisary et al [180] have shown that neurosteroids require a membranous route of access to transmembrane-domain binding sites that might have implications for the design of novel neuroactive steroids because their lipid solubility and related accessibility are probably the key determinants of receptor modulation [180]. This also suggests that by virtue of their high lipid solubility, µM concentrations of neurosteroids may be achieved locally [31].…”

Effects of neurosteroids on a model membrane including cholesterol: A micropipette aspiration study

“…To do this, we exploited the micropipette aspiration technique (MAT), concentrating on giant unilamellar vesicle (GUV) model systems. The neurosteroids that we concentrated on are allopregnanolone (in the following Allo), an endogenous highly lipophilic molecule [20], known to modulate GABA A receptor activity [21,22] and one of its isoform isoallopregnanolone (in the following isoAllo). In particular, Allo potentiates GABA-evoked currents mediated by GABA A receptor activation at low nanomolar concentrations and is able by itself to activate the GABA A receptor at higher concentrations [23].…”