STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit

Sci Rep. 2016 Nov 18;6:36684. doi: 10.1038/srep36684.

Abstract

N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+ buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+ buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+ dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Neuronal Plasticity
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Rats
  • Rats, Wistar
  • Receptor, Muscarinic M1 / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • src-Family Kinases / metabolism*

Substances

  • Receptor, Muscarinic M1
  • Receptors, G-Protein-Coupled
  • Receptors, N-Methyl-D-Aspartate
  • src-Family Kinases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ptpn5 protein, rat
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • N-methyl D-aspartate receptor subtype 2A