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Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations
B. Kysilov, B. Hrcka Krausova, V. Vyklicky, T. Smejkalova, M. Korinek, M. Horak, H. Chodounska, E. Kudova, J. Cerny, L. Vyklicky
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1968 to 1 year ago
Europe PubMed Central
from 1968 to 1 year ago
Medline Complete (EBSCOhost)
from 2002-01-01 to 1 year ago
Wiley Free Content
from 1997 to 1 year ago
PubMed
35318645
DOI
10.1111/bph.15841
Knihovny.cz E-resources
- MeSH
- Rats MeSH
- Mutation MeSH
- Autism Spectrum Disorder * MeSH
- Pregnanes pharmacology MeSH
- Receptors, N-Methyl-D-Aspartate * genetics MeSH
- Steroids MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
3rd Faculty of Medicine Charles University Prague Prague 10 Czech Republic
Institute of Organic Chemistry and Biochemistry CAS Prague 6 Czech Republic
References provided by Crossref.org
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