PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61

Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):E4736-44. doi: 10.1073/pnas.1609702113. Epub 2016 Jul 25.


Phosphorylation regulates surface and synaptic expression of NMDA receptors (NMDARs). Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal-enriched protein tyrosine phosphatase (STEP) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472, which is a critical residue that mediates NMDAR endocytosis. STEP reduces the surface expression of NMDARs by promoting dephosphorylation of GluN2B Y1472, whereas the synaptic scaffolding protein postsynaptic density protein 95 (PSD-95) stabilizes the surface expression of NMDARs. However, nothing is known about a potential functional interaction between STEP and PSD-95. We now report that STEP61 binds to PSD-95 but not to other PSD-95 family members. We find that PSD-95 expression destabilizes STEP61 via ubiquitination and degradation by the proteasome. Using subcellular fractionation, we detect low amounts of STEP61 in the PSD fraction. However, STEP61 expression in the PSD is increased upon knockdown of PSD-95 or in vivo as detected in PSD-95-KO mice, demonstrating that PSD-95 excludes STEP61 from the PSD. Importantly, only extrasynaptic NMDAR expression and currents were increased upon STEP knockdown, as is consistent with low STEP61 localization in the PSD. Our findings support a dual role for PSD-95 in stabilizing synaptic NMDARs by binding directly to GluN2B but also by promoting synaptic exclusion and degradation of the negative regulator STEP61.

Keywords: NMDA receptor; PSD-95; STEP; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disks Large Homolog 4 Protein / physiology*
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Proteasome Endopeptidase Complex / physiology
  • Protein Tyrosine Phosphatases, Non-Receptor / analysis
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Ubiquitination


  • Disks Large Homolog 4 Protein
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • PTPN5 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Proteasome Endopeptidase Complex