G protein-associated, specific membrane binding sites mediate the neuroprotective effect of dehydroepiandrosterone

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dc.contributor.authorCharalampopoulos, I.en
dc.contributor.authorAlexaki, V. I.en
dc.contributor.authorLazaridis, I.en
dc.contributor.authorDermitzaki, E.en
dc.contributor.authorAvlonitis, N.en
dc.contributor.authorTsatsanis, C.en
dc.contributor.authorCalogeropoulou, T.en
dc.contributor.authorMargioris, A. N.en
dc.contributor.authorCastanas, E.en
dc.contributor.authorGravanis, A.en
dc.date.accessioned2015-11-24T19:15:10Z
dc.date.available2015-11-24T19:15:10Z
dc.identifier.issn1530-6860-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/21468
dc.rightsDefault Licence-
dc.subjectAdrenal Medulla/cytologyen
dc.subjectAndrogens/pharmacologyen
dc.subjectAnimalsen
dc.subjectApoptosis/drug effectsen
dc.subjectCell Membrane/drug effectsen
dc.subjectChromaffin Cells/drug effects/metabolismen
dc.subjectCulture Media, Serum-Free/pharmacologyen
dc.subjectDehydroepiandrosterone/analogs & derivatives/metabolism/*pharmacologyen
dc.subjectEstrogens/pharmacologyen
dc.subjectGlucocorticoids/pharmacologyen
dc.subjectGuanosine 5'-O-(3-Thiotriphosphate)/metabolismen
dc.subjectHippocampus/cytology/drug effectsen
dc.subjectHumansen
dc.subjectMaleen
dc.subjectMicroscopy, Confocalen
dc.subjectNeuroprotective Agents/metabolism/*pharmacologyen
dc.subjectPC12 Cells/drug effectsen
dc.subjectPertussis Toxin/pharmacologyen
dc.subjectProto-Oncogene Proteins c-bcl-2/physiologyen
dc.subjectRatsen
dc.subjectReceptors, G-Protein-Coupled/*drug effects/metabolismen
dc.subjectReceptors, GABA-A/physiologyen
dc.subjectReceptors, N-Methyl-D-Aspartate/physiologyen
dc.subjectReceptors, Steroid/*drug effects/metabolismen
dc.subjectSerum Albumin, Bovine/pharmacologyen
dc.subjectbcl-X Protein/physiologyen
dc.titleG protein-associated, specific membrane binding sites mediate the neuroprotective effect of dehydroepiandrosteroneen
heal.abstractThe neurosteroid dehydroepiandrosterone (DHEA) at 1 nM protects NMDA-/GABAA-receptor negative neural crest-derived PC12 cells from apoptosis. We now report that membrane-impermeable DHEA-BSA conjugate replaces unconjugated DHEA in protecting serum-deprived PC12 cells from apoptosis (IC50=1.5 nM). Protection involves phosphorylation of the prosurvival factor Src and induction of the anti-apoptotic protein Bcl-2 and is sensitive to pertussis toxin. Binding assays of [3H]DHEA on isolated PC12 cell membranes revealed saturation within 30 min and binding of DHEA with a Kd of 0.9 nM. A similar binding activity was detectable in isolated membranes from rat hippocampus and from normal human adrenal chromaffin cells. The presence of DHEA-specific membrane binding sites was confirmed by flow cytometry and confocal laser microscopy of DHEA-BSA-FITC stained cells. In contrast to estrogens and progestins, glucocorticoids and androgens displaced DHEA from its membrane binding sites but with a 10-fold lower affinity than DHEA (IC50=9.3 and 13.6 nM, respectively). These agents acted as pure antagonists, blocking the antiapoptotic effect of DHEA as well as the induction of Bcl-2 proteins and Src kinase activation. In conclusion, our findings suggest that neural crest-derived cells possess specific DHEA membrane binding sites coupled to G proteins. Binding to these sites confers neuroprotection.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1096/fj.05-5078fje-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/16407456-
heal.identifier.secondaryhttp://www.fasebj.org/content/early/2006/03/01/fj.05-5078fje.full.pdf-
heal.journalNameFaseb Journalen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2006-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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