title: Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis.
abstract: The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75(NTR) membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [(3)H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75(NTR) receptors (K(D): 7.4 ± 1.75 nM and 5.6 ± 0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75(NTR) receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75(NTR) receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Iakovos
authors.initials: I
authors.lastname: Lazaridis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.forename: Vassilia-Ismini
authors.initials: VI
authors.lastname: Alexaki
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Avlonitis
authors.forename: Iosif
authors.initials: I
authors.lastname: Pediaditakis
authors.forename: Paschalis
authors.initials: P
authors.lastname: Efstathopoulos
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
mesh_terms: D000818:Animals; D017209:Apoptosis; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000473:pathology*; D016716:PC12 Cells; D010766:Phosphorylation; D010802:Phylogeny; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017475:Receptors, Nerve Growth Factor; D003687:Dehydroepiandrosterone; D020917:Receptor, trkA