Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations.
Autor: | Kysilov B; Institute of Physiology CAS, Prague 4, Czech Republic.; Third Faculty of Medicine, Charles University in Prague, Prague 10, Czech Republic., Hrcka Krausova B; Institute of Physiology CAS, Prague 4, Czech Republic., Vyklicky V; Institute of Physiology CAS, Prague 4, Czech Republic., Smejkalova T; Institute of Physiology CAS, Prague 4, Czech Republic., Korinek M; Institute of Physiology CAS, Prague 4, Czech Republic., Horak M; Institute of Physiology CAS, Prague 4, Czech Republic., Chodounska H; Institute of Organic Chemistry and Biochemistry CAS, Prague 6, Czech Republic., Kudova E; Institute of Organic Chemistry and Biochemistry CAS, Prague 6, Czech Republic., Cerny J; Institute of Physiology CAS, Prague 4, Czech Republic., Vyklicky L; Institute of Physiology CAS, Prague 4, Czech Republic. |
---|---|
Jazyk: | angličtina |
Zdroj: | British journal of pharmacology [Br J Pharmacol] 2022 Aug; Vol. 179 (15), pp. 3970-3990. Date of Electronic Publication: 2022 Apr 08. |
DOI: | 10.1111/bph.15841 |
Abstrakt: | Background and Purpose: N-methyl-D-aspartate receptors (NMDARs) play a critical role in synaptic plasticity, and mutations in human genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. Compounds with a positive allosteric effect are thought to compensate for reduced receptor function. Experimental Approach: We have used whole-cell patch-clamp electrophysiology on recombinant rat NMDARs and human variants found in individuals with neuropsychiatric disorders, in combination with in silico modelling, to explore the site of action of novel epipregnanolone-based NMDAR modulators. Key Results: Analysis of the action of 4-(20-oxo-5β-pregnan-3β-yl) butanoic acid (EPA-But) at the NMDAR indicates that the effect of this steroid with a "bent" structure is different from that of cholesterol and oxysterols and shares a disuse-dependent mechanism of NMDAR potentiation with the "planar" steroid 20-oxo-pregn-5-en-3β-yl sulfate (PE-S). The potentiating effects of EPA-But and PE-S are additive. Alanine scan mutagenesis identified residues that reduce the potentiating effect of EPA-But. No correlation was found between the effects of EPA-But and PE-S at mutated receptors that were less sensitive to either steroid. The relative degree of potentiation induced by the two steroids also differed in human NMDARs carrying rare variants of hGluN1 or hGluN2B subunits found in individuals with neuropsychiatric disorders, including intellectual disability, epilepsy, developmental delay, and autism spectrum disorder. Conclusion and Implications: Our results show novel sites of action for pregnanolones at the NMDAR and provide an opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with glutamatergic system hypofunction. (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.) |
Databáze: | MEDLINE |
Externí odkaz: | |
Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |