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Regulation of GluR2 promoter activity by neurotrophic factors via a neuron‐restrictive silencer element
Author(s) -
Brené Stefan,
Messer Chad,
Okado Haruo,
Hartley Melissa,
Heinemann Stephen F.,
Nestler Eric J.
Publication year - 2000
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2000.00040.x
Subject(s) - glial cell line derived neurotrophic factor , neurotrophic factors , biology , gdnf family of ligands , ampa receptor , microbiology and biotechnology , promoter , transcription factor , silencer , gene expression , gene , glutamate receptor , receptor , genetics , mechanical engineering , engineering , inlet
The AMPA glutamate receptor subunit GluR2, which plays a critical role in regulation of AMPA channel function, shows altered levels of expression in vivo after several chronic perturbations. To evaluate the possibility that transcriptional mechanisms are involved, we studied a 1254‐nucleotide fragment of the 5′‐promoter region of the mouse GluR2 gene in neural‐derived cell lines. We focused on regulation of GluR2 promoter activity by two neurotrophic factors, which are known to be altered in vivo in some of the same systems that show GluR2 regulation. Glial‐cell line derived neurotrophic factor (GDNF) and brain‐derived neurotrophic factor (BDNF) both induced GluR2 promoter activity. This was associated with increased expression of endogenous GluR2 immunoreactivity in the cells as measured by Western blotting. The effect of GDNF and BDNF appeared to be mediated via a NRSE (neuron‐restrictive silencer element) present within the GluR2 promoter. The response to these neurotrophic factors was lost upon mutating or deleting this site, but not several other putative response elements present within the promoter. Moreover, overexpression of REST (restrictive element silencer transcription factor; also referred to as NRSF or neuron restrictive silencer factor), which is known to act on NRSEs in other genes to repress gene expression, blocked the ability of GDNF to induce GluR2 promoter activity. However, GDNF did not alter endogenous levels of REST in the cells. Together, these findings suggest that GluR2 expression can be regulated by neurotrophic factors via an apparently novel mechanism involving the NRSE present within the GluR2 gene promoter.