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G protein‐associated, specific membrane binding sites mediate the neuroprotective effect of dehydroepiandrosterone
Author(s) -
Charalampopoulos Ioannis,
Alexaki VassiliaIsmini,
Lazaridis Iakovos,
Dermitzaki Erene,
Avlonitis Nicolaos,
Tsatsanis Christos,
Calogeropoulou Theodora,
Margioris Andrew N.,
Castanas Elias,
Gravanis Achille
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5078fje
Subject(s) - dehydroepiandrosterone , neuroprotection , chemistry , apoptosis , microbiology and biotechnology , endocrinology , medicine , biology , biochemistry , pharmacology , hormone , androgen
The 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 [ 3 H]DHEA on isolated PC12 cell membranes revealed saturation within 30 min and binding of DHEA with a K d 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.

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