G protein-associated, specific membrane binding sites mediate the neuroprotective effect of dehydroepiandrosterone
Φόρτωση...
Ημερομηνία
Συγγραφείς
Charalampopoulos, I.
Alexaki, V. I.
Lazaridis, I.
Dermitzaki, E.
Avlonitis, N.
Tsatsanis, C.
Calogeropoulou, T.
Margioris, A. N.
Castanas, E.
Gravanis, A.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Faseb Journal
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
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 [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.
Περιγραφή
Λέξεις-κλειδιά
Adrenal Medulla/cytology, Androgens/pharmacology, Animals, Apoptosis/drug effects, Cell Membrane/drug effects, Chromaffin Cells/drug effects/metabolism, Culture Media, Serum-Free/pharmacology, Dehydroepiandrosterone/analogs & derivatives/metabolism/*pharmacology, Estrogens/pharmacology, Glucocorticoids/pharmacology, Guanosine 5'-O-(3-Thiotriphosphate)/metabolism, Hippocampus/cytology/drug effects, Humans, Male, Microscopy, Confocal, Neuroprotective Agents/metabolism/*pharmacology, PC12 Cells/drug effects, Pertussis Toxin/pharmacology, Proto-Oncogene Proteins c-bcl-2/physiology, Rats, Receptors, G-Protein-Coupled/*drug effects/metabolism, Receptors, GABA-A/physiology, Receptors, N-Methyl-D-Aspartate/physiology, Receptors, Steroid/*drug effects/metabolism, Serum Albumin, Bovine/pharmacology, bcl-X Protein/physiology
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/16407456
http://www.fasebj.org/content/early/2006/03/01/fj.05-5078fje.full.pdf
http://www.fasebj.org/content/early/2006/03/01/fj.05-5078fje.full.pdf
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής