Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP 61

Mol Neurobiol. 2018 Apr;55(4):3096-3111. doi: 10.1007/s12035-017-0555-x. Epub 2017 May 2.

Abstract

NMDA receptor signaling is critical for the development of synaptic plasticity, learning, and memory, and dysregulation of NMDAR signaling is implicated in a number of neurological disorders including schizophrenia (SZ). Previous work has demonstrated that the STriatal-Enriched protein tyrosine Phosphatase 61 kDa (STEP61) is elevated in human SZ postmortem cortical samples and after administration of psychotomimetics to cultures or mice. Here, we report that activation of synaptic NMDAR by bicuculline or D-serine results in the ubiquitination and proteasomal degradation of STEP61, and increased surface localization of GluN1/GluN2B receptors. Moreover, bicuculline or D-serine treatments rescue the motor and cognitive deficits in MK-801-treated mice and reduce STEP61 in mouse frontal cortex. These results suggest that STEP61 may contribute to the therapeutic effects of D-serine.

Keywords: Cognitive function; D-serine; NMDA receptor; STEP61; Schizophrenia; Ubiquitination.

MeSH terms

  • Animals
  • Bicuculline / pharmacology
  • Cells, Cultured
  • Disks Large Homolog 4 Protein / metabolism
  • Lipoylation
  • Male
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Proteolysis* / drug effects
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Substrate Specificity / drug effects
  • Synapses / drug effects
  • Synapses / metabolism*
  • Ubiquitination* / drug effects

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Receptors, N-Methyl-D-Aspartate
  • Phosphotyrosine
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ptpn5 protein, rat
  • striatal-enriched tyrosine phosphatase 61, mouse
  • Bicuculline