서영호 (서울대학교 의과대학)

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서울대학교 의과대학

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Proc. Natl. Acad. Sci. USA, Apr 30 2024, 121 (18) | https://doi.org/10.1073/pnas.2316819121 SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD

Sanghyeon Lee^a,b,c,1, Jungho Kim^a,b,c,1, Hyun-Hee Ryu^a,b,d,1, Hanbyul Jang^a,b,d, DoEun Lee^a,b,c, Seungha Lee^a,b,c, Jae-man Song^a,b,c, Yong-Seok Lee^a,b,d,2, and Young Ho Suh^a,b,c,2

^aDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea;

^bNeuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea;

^cTransplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea;

^dDepartment of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea

¹Sanghyeon Lee, J.K., and H.- H.R. contributed equally to this work.

²To whom correspondence may be addressed.

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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-25)
연구진국내 연구진
분야 의약학 > 신경의학

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