Dataset Information

Pregnenolone sulfate analogues differentially modulate GABA_A receptor closed/desensitised states.

ABSTRACT:

Background and purpose

GABA_A receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate.

Experimental approach

New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABA_A receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations.

Key results

All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six- (compound 5) or five-membered heterocyclic ring (compound 6) on C-21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABA_A receptor, are the most likely cause of the distinctive functional profiles.

Conclusions and implications

Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next-generation GABA_A receptor drug design and development.

SUBMITTER: Mortensen M

PROVIDER: S-EPMC10952582 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Pregnenolone sulfate analogues differentially modulate GABA<sub>A</sub> receptor closed/desensitised states.

Mortensen Martin M Xu Yue Y Shehata Mohamed A MA Krall Jacob J Ernst Margot M Frølund Bente B Smart Trevor G TG

British journal of pharmacology 20230602 19

<h4>Background and purpose</h4>GABA<sub>A</sub> receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate.<h4>Experimental approach</h4>New pregnenolone sulfate analogues were synthesised incorporating vario ...[more]

PMID: 37194503

Similar Datasets

Project description:BackgroundNeurosteroids have various physiological and neuropsychopharmacological effects. In addition to the genomic effects of steroids, some neurosteroids modulate several neurotransmitter receptors and channels, such as N-methyl-D-aspartate receptors, gamma-aminobutyric acid type A (GABA(A)) receptors, and sigma(1) receptors, and voltage-gated Ca(2+) and K(+) channels. However, the molecular mechanisms underlying the various effects of neurosteroids have not yet been sufficiently clarified. In the nervous system, inwardly rectifying K(+) (Kir) channels also play important roles in the control of resting membrane potential, cellular excitability and K(+) homeostasis. Among constitutively active Kir2 channels in a major Kir subfamily, Kir2.3 channels are expressed predominantly in the forebrain, a brain area related to cognition, memory, emotion, and neuropsychiatric disorders.Methodology/principal findingsThe present study examined the effects of various neurosteroids on Kir2.3 channels using the Xenopus oocyte expression assay. In oocytes injected with Kir2.3 mRNA, only pregnenolone sulfate (PREGS), among nine neurosteroids tested, reversibly potentiated Kir2.3 currents. The potentiation effect was concentration-dependent in the micromolar range, and the current-voltage relationship showed inward rectification. However, the potentiation effect of PREGS was not observed when PREGS was applied intracellularly and was not affected by extracellular pH conditions. Furthermore, although Kir1.1, Kir2.1, Kir2.2, and Kir3 channels were insensitive to PREGS, in oocytes injected with Kir2.1/Kir2.3 or Kir2.2/Kir2.3 mRNA, but not Kir2.1/Kir2.2 mRNA, PREGS potentiated Kir currents. These potentiation properties in the concentration-response relationships were less potent than for Kir2.3 channels, suggesting action of PREGS on Kir2.3-containing Kir2 heteromeric channels.Conclusions/significanceThe present results suggest that PREGS acts as a positive modulator of Kir2.3 channels. Kir2.3 channel potentiation may provide novel insights into the various effects of PREGS.

Dataset Information

Pregnenolone sulfate analogues differentially modulate GABA_A receptor closed/desensitised states.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Pregnenolone sulfate analogues differentially modulate GABA<sub>A</sub> receptor closed/desensitised states.

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Dataset Information

Pregnenolone sulfate analogues differentially modulate GABAA receptor closed/desensitised states.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Pregnenolone sulfate analogues differentially modulate GABA<sub>A</sub> receptor closed/desensitised states.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pregnenolone sulfate analogues differentially modulate GABA_A receptor closed/desensitised states.