SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD

Proc Natl Acad Sci U S A. 2024 Apr 30;121(18):e2316819121. doi: 10.1073/pnas.2316819121. Epub 2024 Apr 24.

Abstract

Posttranslational modifications regulate the properties and abundance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that mediate fast excitatory synaptic transmission and synaptic plasticity in the central nervous system. During long-term depression (LTD), protein tyrosine phosphatases (PTPs) dephosphorylate tyrosine residues in the C-terminal tail of AMPA receptor GluA2 subunit, which is essential for GluA2 endocytosis and group I metabotropic glutamate receptor (mGluR)-dependent LTD. However, as a selective downstream effector of mGluRs, the mGluR-dependent PTP responsible for GluA2 tyrosine dephosphorylation remains elusive at Schaffer collateral (SC)-CA1 synapses. In the present study, we find that mGluR5 stimulation activates Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) by increasing phospho-Y542 levels in SHP2. Under steady-state conditions, SHP2 plays a protective role in stabilizing phospho-Y869 of GluA2 by directly interacting with GluA2 phosphorylated at Y869, without affecting GluA2 phospho-Y876 levels. Upon mGluR5 stimulation, SHP2 dephosphorylates GluA2 at Y869 and Y876, resulting in GluA2 endocytosis and mGluR-LTD. Our results establish SHP2 as a downstream effector of mGluR5 and indicate a dual action of SHP2 in regulating GluA2 tyrosine phosphorylation and function. Given the implications of mGluR5 and SHP2 in synaptic pathophysiology, we propose SHP2 as a promising therapeutic target for neurodevelopmental and autism spectrum disorders.

Keywords: GluA2; SHP2; mGluR-LTD; mGluR5; trafficking.

Publication types

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

MeSH terms

  • Animals
  • Endocytosis* / physiology
  • Humans
  • Long-Term Synaptic Depression* / physiology
  • Mice
  • Neurons / metabolism
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11* / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11* / metabolism
  • Rats
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Receptors, AMPA* / metabolism
  • Receptors, Metabotropic Glutamate* / metabolism
  • Synapses / metabolism
  • Tyrosine / metabolism

Substances

  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 2
  • Receptors, Metabotropic Glutamate
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Tyrosine
  • Receptor, Metabotropic Glutamate 5