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Molecular mechanisms for nanomolar concentrations of neurosteroids at NR1/NR2B receptors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2008 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 324, no 2, 759-768 p.Article in journal (Refereed) Published
Abstract [en]

Neurosteroids are endogenous steroids acting in the central nervous system. They participate in synaptic plasticity, memory and learning, Alzheimer's disease, and certain drug reward. Some mechanisms behind these effects are thought to be nongenomic, e. g., they modulate the function of the N-methyl-D-aspartate (NMDA) receptor complex. In this study, we used a Chinese hamster ovary cell line stably transfected with NMDA receptor constituents NR1/NR2B, to investigate the effects of nanomolar concentrations of the neurosteroids pregnenolone sulfate (PS) and pregnanolone sulfate (3 alpha 5 beta S) on binding of the radioligand [H-3] ifenprodil. Neither of the steroids displaced [H-3] ifenprodil, but both induced a shift in its fit from one to two binding sites. The effects of the neurosteroids were also measured as changes in intracellular calcium ([Ca2+](i)) after glutamate stimulation. Although the steroids did not alter the response to glutamate, they influenced the extent of ifenprodil blockade of the receptor: PS increased and 3 alpha 5 beta S decreased this effect. The coincubation of several NMDA receptor ligands in the assay indicated that PS and 3 alpha 5 beta S act via different binding sites from those for glutamate, glycine, and dithiothreitol. Combining the two steroids revealed that they do not share a common binding site. In conclusion, these results substantiate previous evidence of the allosteric modulatory effect induced by PS and 3 alpha 5 beta S on NMDA receptors at nanomolar concentrations. The neurosteroid-mediated modulation of the receptor is also reflected in an altered glutamate stimulated [Ca2+](i), in response to ifenprodil.

Place, publisher, year, edition, pages
2008. Vol. 324, no 2, 759-768 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96824DOI: 10.1124/jpet.107.130518ISI: 000252633200038OAI: oai:DiVA.org:uu-96824DiVA: diva2:171529
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Neurosteroids Induce Allosteric Effects on the NMDA Receptor: Nanomolar Concentrations of Neurosteroids Exert Non-Genomic Effects on the NMDA Receptor Complex
Open this publication in new window or tab >>Neurosteroids Induce Allosteric Effects on the NMDA Receptor: Nanomolar Concentrations of Neurosteroids Exert Non-Genomic Effects on the NMDA Receptor Complex
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The neurosteroids constitute a group of powerful hormones synthesized and acting in the central nervous system. They participate in a number of important central processes, such as memory and learning, mood and neuroprotection. Their effects emerge from rapid interactions with membrane bound receptors, such as the N-methyl-D-aspartate (NMDA) receptor, the gamma-amino-butyric acid receptor and the sigma 1 receptor. The mechanisms of action are separate from classical genomic interactions.

The aims of this thesis were to identify and characterize the molecular mechanisms underlying the effects of nanomolar concentrations of neurosteroids at the NMDA receptor.

The results show that the neurosteroids pregnenolone sulfate (PS) and pregnanolone sulfate 3α5βS) differently modulate the NMDA receptor, changing the kinetics for the NMDA receptor antagonist ifenprodil, through unique and separate targets at the NR2B subunit. The effects that appear to be temperature independent were further confirmed in a calcium imagining functional assay. A second functional study demonstrated that PS and 3α5βS affect glutamate-stimulated neurite outgrowth in NG108-15 cells.

Misuse of anabolic androgenic steroids (AAS) has powerful effects on emotional states. Since neurosteroids regulate processes involved in mood it can be hypothesised that AAS can interact with the action of neurosteroids in the brain. However, chronic administration of the AAS nandrolone decanoate did not alter the allosteric effects of PS or 3α5βS at the NMDA receptor, but changed the affinity for PS, 3α5βS and dehydroepiandrosterone sulfate to the sigma 1 receptor. The results also showed that the neurosteroids displace 3H-ifenprodil from the sigma 1 and 2 receptors without directly sharing the binding site for 3H-ifenprodil at the sigma 1 receptor. The decreased affinity for the neurosteroids at the sigma 1 receptor may be involved in the depressive symptoms associated with AAS misuse.

The NMDA receptor system is deeply involved in neurodegeneration and the NMDA receptor antagonist ifenprodil exert neuroprotective actions. The findings that neurosteroids interact with ifenprodil at the NMDA receptor may be an opportunity to obtain synergistic effects in neuroprotective treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 69
Keyword
Pharmaceutical pharmacology, Pharmacology, neurosteroids, NMDA receptor, NR2B subunit, ifenprodil, sigma receptor, anabolic androgenic steroids, allosteric modulation, non-genomic, Farmaceutisk farmakologi
Identifiers
urn:nbn:se:uu:diva-8503 (URN)978-91-554-7114-9 (ISBN)
Public defence
2008-04-04, B22, BMC, Husargatan, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-03-14 Created: 2008-03-14Bibliographically approved

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