RGD Reference Report - Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis. - Rat Genome Database

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Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis.

Authors: Lazaridis, I  Charalampopoulos, I  Alexaki, VI  Avlonitis, N  Pediaditakis, I  Efstathopoulos, P  Calogeropoulou, T  Castanas, E  Gravanis, A 
Citation: Lazaridis I, etal., PLoS Biol. 2011 Apr;9(4):e1001051. doi: 10.1371/journal.pbio.1001051. Epub 2011 Apr 26.
RGD ID: 8554787
Pubmed: PMID:21541365   (View Abstract at PubMed)
PMCID: PMC3082517   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pbio.1001051   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of neuron apoptotic process involved_inIMP 8554787; 8554787PMID:21541365UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:Q9Y4K38554787PMID:21541365IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Ngf  (nerve growth factor)
Ngfr  (nerve growth factor receptor)
Ntrk1  (neurotrophic receptor tyrosine kinase 1)


Additional Information