Pregnane neurosteroids exert opposite effects on GABA and glycine-induced chloride current in isolated rat neurons

0558551 - ÚOCHB 2023 RIV US eng J - Článek v odborném periodiku
Solntseva, E. I. - Bukanova, J. V. - Skrebitsky, V. G. - Kudová, Eva
Pregnane neurosteroids exert opposite effects on GABA and glycine-induced chloride current in isolated rat neurons.
Hippocampus. Roč. 32, č. 7 (2022), s. 552-563. ISSN 1050-9631. E-ISSN 1098-1063
Grant CEP: GA MZd(CZ) EF16_025/0007444
Institucionální podpora: RVO:61388963
Klíčová slova: GABA(A) receptor * glycine receptor * neurosteroid * pregnane * structure-activity relationship study
Obor OECD: Neurosciences (including psychophysiology
Impakt faktor: 3.5, rok: 2022
Způsob publikování: Omezený přístup
https://doi.org/10.1002/hipo.23449

The ability of endogenous neurosteroids (NSs) with pregnane skeleton modified at positions C-3 and C-5 to modulate the functional activity of inhibitory glycine receptors (GlyR) and ionotropic ɣ-aminobutyric acid receptors (GABAAR) was estimated. The glycine and GABA-induced chloride current (IGly and IGABA) were measured in isolated pyramidal neurons of the rat hippocampus and in isolated rat cerebellar Purkinje cells, respectively. Our experiments demonstrated that pregnane NSs affected IGABA and IGly in a different manner. At low concentrations (up to 5 μM), tested pregnane NSs increased or did not change the peak amplitude of the IGABA, but reduced the IGly by decreasing the peak amplitude and/or accelerating desensitization. Namely, allopregnanolone (ALLO), epipregnanolone (EPI), pregnanolone (PA), pregnanolone sulfate (PAS) and 5β-dihydroprogesterone (5β-DHP) enhanced the IGABA in Purkinje cells. Dose–response curves plotted in the concentration range from 1 nM to 100 μM were smooth for EPI and 5β-DHP, but bell-shaped for ALLO, PA and PAS. The peak amplitude of the IGly was reduced by PA, PAS, and 5α- and 5β-DHP. In contrast, ALLO, ISO and EPI did not modulate it. Dose–response curves for the inhibition of the IGly peak amplitude were smooth for all active compounds. All NSs accelerated desensitization of the IGly. The dose–response relationship for this effect was smooth for ALLO, PA, PAS and 5β-DHP, but it was U-shaped for EPI, 5α-DHP and ISO. These results, together with our previous results on NSs with androstane skeleton, offer comprehensive overview for understanding the mechanisms of effects of NSs on IGly and IGABA.
Trvalý link: http://hdl.handle.net/11104/0332190