Modulation of GABA and glycine receptors in rat pyramidal hippocampal neurones by 3 alpha 5 beta-pregnanolone derivatives

0492171 - ÚOCHB 2019 RIV GB eng J - Článek v odborném periodiku
Bukanova, J. V. - Solntseva, E. I. - Kolbaev, S. N. - Kudová, Eva
Modulation of GABA and glycine receptors in rat pyramidal hippocampal neurones by 3 alpha 5 beta-pregnanolone derivatives.
Neurochemistry International. Roč. 118, Sep (2018), s. 145-151. ISSN 0197-0186. E-ISSN 1872-9754
Grant CEP: GA TA ČR(CZ) TE01020028
Institucionální podpora: RVO:61388963
Klíčová slova: neurosteroid * GABA receptor * glycine receptor * pregnanolone * structure-activity relationship
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 3.994, rok: 2018

The ability of pregnanolone glutamate (PA-Glu), pregnanolone hemisuccinate (PA-hSuc) and pregnanolone hemipimelate (PA-hPim), neuroactive steroids with a negative modulatory effect on excitatory N-methyl-D-aspartate receptors, to influence the functional activity of inhibitory gamma-aminobutyric acid and glycine receptors was estimated. The GABA- and glycine-induced chloride currents (I-GABA and I-Gly) were measured in isolated pyramidal neurons of the rat hippocampus using the patch-clamp technique. Compound PA-Glu was found to potentiate I-GABA and to inhibit loy, while PA-hSuc and PA-hPim inhibited both I-GABA and I-Gly. Moreover, PA-Glu, PA-hSuc, and PA-hPim had a greater effect on desensitization than on the peak amplitude of I-Gly. At a high concentration of glycine (500 mu M), the effect of neurosteroids on the peak amplitude of I-Gly disappeared, and the acceleration of desensitization remained. The conversion of PA-Glu into androstane glutamate (AND-Glu), an analogue that lacks the C-17 acetyl moiety, completely eliminated the effects on these receptors. Our results indicate that the C-17 acetyl moiety is crucial for the action on I-GABA and I-Gly. Our results indicate that the pregnanolone derivatives, in contrast to the androstane analogues, modulate I-GABA and I-Gly at low micromolar concentrations and this family of neurosteroids can be useful for future structure-activity relationship studies of the steroid modulation of other receptor types.
Trvalý link: http://hdl.handle.net/11104/0285725