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

• 成果类型: Article
• 署名作者: Lee, Sanghyeon; Kim, Jungho; Ryu, Hyun-Hee; Jang, Hanbyu; Lee, Doeun; Lee, Seungha; Song, Jae-man; Lee, Yong-Seok; Suh, Young Ho
• 署名单位: Seoul National University (SNU); Seoul National University (SNU); Seoul National University (SNU); Seoul National University (SNU)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12827
• DOI: 10.1073/pnas.2316819121
• 发表日期: 2024-04-24
• 关键词: long-term depression; activated protein-kinase; ca1 region; area ca1; glutamate receptors; synaptic plasticity; crystal-structure; phosphatase step; rat hippocampus; induction

摘要

Posttranslational modifications regulate the properties and abundance of synaptic alpha- 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) domaincontaining 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.