biostudies-literatureLee SKorea Dementia Research CenterNational Research Foundation of Korea (NRF)Korea Dementia Research Center (KDRC)National Research Foundation of Koreae2316819121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11066993biostudies-literatureUnknown121(18)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) doProceedings of the National Academy of Sciences of the United States of AmericaSHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.PMC11066993NRF-2020R1A5A1019023NRF-2023R1A2C2003229NRF-2022R1A2C1004913NRF-2018R1A5A2025964HU21C0071NRF-2018R1A2B6004759Lee YSLee SSong JMJang HKim JSuh YHRyu HHLee DfalseSHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.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) do2024-01-01T00:00:00Z2024 Apr2025-04-04T02:57:24.082Z2025-04-04T02:57:24.082ZS-EPMC110669933865704210.1073/pnas.2316819121