3β-hydroxysteroids and pregnenolone sulfate inhibit recombinant rat GABAA receptor through different channel property

Wang, Mingde; Rahman, Mozibur; Zhu, Di; Johansson, Ingvar; Bäckström, Torbjörn

doi:10.1016/j.ejphar.2006.11.071

Cited by 21 publications

(18 citation statements)

References 31 publications

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“…3β-Hydroxysteroids however, inhibit GABA a receptor activity in a manner independent of desensitization kinetics while PS aids in slowing the desensitization of receptors. In this context, PS is a more potent modulator than the 3β-hydroxysteroids (Wang et al, 2007). …”

Section: Neurosteroid Modulation Of Gabaa Receptorsmentioning

confidence: 99%

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

2013

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Rationale Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal GABAa receptors are one of the prime molecular targets of neurosteroids. Objective This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAa receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAa receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAa receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAa receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. Conclusion The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAa receptors provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.

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Section: Neurosteroid Modulation Of Gabaa Receptorsmentioning

confidence: 99%

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

2013

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“…Conversely, for peak GABA current inhibition, the PS IC 50 is decreased. Reduced or abolished inhibitory effects of PS on GABA currents have been reported for α1 V256S β2γ2L and α1β2 A252S γ2L receptors ( Wang et al., 2006 , 2007 ). This supports the notion that mutating either the α1 or β2/3 subunits at the 2′ position reduces the potency and efficacy of PS.…”

Section: Discussionmentioning

confidence: 90%

“…Interestingly, α1 V256S , but not β2 A252S , eliminates GABA A R inhibition by the 3β-hydroxypregnane steroids ( Seljeset et al., 2015 , Wang et al., 2002 , 2007 ). These are diastereomers of the potentiating 3α-hydroxypregnane steroids, but are similar to the sulphated neurosteroids in that they non-competitively inhibit the GABA A R in an activity- or state-dependent manner.…”

Section: Discussionmentioning

confidence: 97%

“…These are diastereomers of the potentiating 3α-hydroxypregnane steroids, but are similar to the sulphated neurosteroids in that they non-competitively inhibit the GABA A R in an activity- or state-dependent manner. In the study by Wang et al. (2007) , desensitisation kinetics were characterised by determining a ratio between peak and steady-state currents (I P /I SS ).…”

Section: Discussionmentioning

confidence: 99%

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Probing GABAA receptors with inhibitory neurosteroids

et al. 2018

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γ-aminobutyric acid type A receptors (GABAARs) are important components of the central nervous system and they are functionally tasked with controlling neuronal excitability. These receptors are subject to post-translational modification and also to modulation by endogenous regulators, such as the neurosteroids. These modulators can either potentiate or inhibit GABAAR function. Whilst the former class of neurosteroids are considered to bind to and act from the transmembrane domain of the receptor, the domains that are important for the inhibitory neurosteroids remain less clear. In this study, we systematically compare a panel of recombinant synaptic-type and extrasynaptic-type GABAARs expressed in heterologous cell systems for their sensitivity to inhibition by the classic inhibitory neurosteroid, pregnenolone sulphate. Generally, peak GABA current responses were inhibited less compared to steady-state currents, implicating the desensitised state in inhibition. Moreover, pregnenolone sulphate inhibition increased with GABA concentration, but showed minimal voltage dependence. There was no strong dependence of inhibition on receptor subunit composition, the exception being the ρ1 receptor, which is markedly less sensitive. By using competition experiments with pregnenolone sulphate and the GABA channel blocker picrotoxinin, discrete binding sites are proposed. Furthermore, by assessing inhibition using site-directed mutagenesis and receptor chimeras comprising α, β or γ subunits with ρ1 subunits, the receptor transmembrane domains are strongly implicated in mediating inhibition and most likely the binding location for pregnenolone sulphate in GABAARs.This article is part of the “Special Issue Dedicated to Norman G. Bowery”.

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“…Furthermore, the learning impairments induced by allopregnanolone can be blocked by concomitant administration of 3β-20β-dihydroxy-5α-pregnane (Turkmen et al 2004), a compound known to inhibit allopregnanolone effects in vitro (Stromberg et al 2006;Wang et al 2007). The dose and/or serum concentration of allopregnanolone appears to be important for its cognitive effects.…”

Section: Discussionmentioning

confidence: 98%