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

Autor:	Lee S; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea., Kim J; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea., Ryu HH; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea., Jang H; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea., Lee D; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea., Lee S; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea., Song JM; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea., Lee YS; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea., Suh YH; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.; Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.; Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 30; Vol. 121 (18), pp. e2316819121. Date of Electronic Publication: 2024 Apr 24.
DOI:	10.1073/pnas.2316819121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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