RGD Reference Report - Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter. - Rat Genome Database

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Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter.

Authors: Numakawa, Tadahiro  Kumamaru, Emi  Adachi, Naoki  Yagasaki, Yuki  Izumi, Aiko  Kunugi, Hiroshi 
Citation: Numakawa T, etal., Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):647-52. doi: 10.1073/pnas.0800888106. Epub 2009 Jan 6.
RGD ID: 13432268
Pubmed: PMID:19126684   (View Abstract at PubMed)
PMCID: PMC2626757   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0800888106   (Journal Full-text)

An increase in glucocorticoid levels and down-regulation of BDNF (brain-derived neurotrophic factor) are supposed to be involved in the pathophysiology of depressive disorders. However, possible crosstalk between glucocorticoid- and BDNF-mediated neuronal functions in the CNS has not been elucidated. Here, we examined whether chronic glucocorticoid exposure influences BDNF-triggered intracellular signaling for glutamate release via a glutamate transporter. We found that chronic exposure to dexamethasone (DEX, a synthetic glucocorticoid) suppressed BDNF-induced glutamate release via weakening the activation of the PLC-gamma (phospholipase C-gamma)/Ca(2+) system in cultured cortical neurons. We demonstrated that the GR (glucocorticoid receptor) interacts with receptor tyrosine kinase for BDNF (TrkB). Following DEX treatment, TrkB-GR interaction was reduced due to the decline in GR expression. Corticosterone, a natural glucocorticoid, also reduced TrkB-GR interaction, BDNF-stimulated PLC-gamma, and BDNF-triggered glutamate release. Interestingly, BDNF-dependent binding of PLC-gamma to TrkB was diminished by DEX. SiRNA transfection to induce a decrease in endogenous GR mimicked the inhibitory action of DEX. Conversely, DEX-inhibited BDNF-activated PLC-gamma signaling for glutamate release was recovered by GR overexpression. We propose that TrkB-GR interaction plays a critical role in the BDNF-stimulated PLC-gamma pathway, which is required for glutamate release, and the decrease in TrkB-GR interaction caused by chronic exposure to glucocorticoids results in the suppression of BDNF-mediated neurotransmitter release via a glutamate transporter.




Molecular Function

  
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Original Reference(s)
Nr3c1Ratprotein binding enablesIPIUniProtKB:Q63604PMID:19126684IntAct 
Ntrk2Ratprotein binding enablesIPIUniProtKB:P06536PMID:19126684IntAct 


Genes (Rattus norvegicus)
Nr3c1  (nuclear receptor subfamily 3, group C, member 1) Ntrk2  (neurotrophic receptor tyrosine kinase 2)