Journal
MOLECULAR NEUROBIOLOGY
Volume 53, Issue 6, Pages 4261-4273Publisher
SPRINGER
DOI: 10.1007/s12035-015-9335-7
Keywords
PLC gamma; GluN2B; ERK1/2; NGF; NT-3; Depolarization; STEP33
Categories
Funding
- Plan Nacional de I+D+I y cofinanciado por el ISCIII-Subdireccion General de Evaluacion y el Fondo Europeo de Desarrollo Regional (FEDER) [PI10/01072, PI13/01250, RD12/0019/0002]
- Ministerio de Ciencia e Innovacion, Spain [SAF2012-39142, SAF2011-29507]
- Generalitat de Catalunya, Spain [2009SGR-00326, AGAUR ST067914]
- National Institutes of Health [MH091037, MH52711]
- Ministerio de Economia y Competitividad, Spain (Juan de la Cierva subprogram) [JCI-2010-08207]
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Brain-derived neurotrophic factor (BDNF) promotes synaptic strengthening through the regulation of kinase and phosphatase activity. Conversely, striatal-enriched protein tyrosine phosphatase (STEP) opposes synaptic strengthening through inactivation or internalization of signaling molecules. Here, we investigated whether BDNF regulates STEP levels/activity. BDNF induced a reduction of STEP61 levels in primary cortical neurons, an effect that was prevented by inhibition of tyrosine kinases, phospholipase C gamma, or the ubiquitin-proteasome system (UPS). The levels of pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204), two STEP substrates, increased in BDNF-treated cultures, and blockade of the UPS prevented STEP61 degradation and reduced BDNF-induced GluN2B and ERK1/2 phosphorylation. Moreover, brief or sustained cell depolarization reduced STEP61 levels in cortical neurons by different mechanisms. BDNF also promoted UPS-mediated STEP61 degradation in cultured striatal and hippocampal neurons. In contrast, nerve growth factor and neurotrophin-3 had no effect on STEP61 levels. Our results thus indicate that STEP61 degradation is an important event in BDNF-mediated effects.
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