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  • The EMBO Journal (2004) 23, 1040 - 1050
  • doi:10.1038/sj.emboj.7600126

Published online: 19 February 2004

Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD

Gholamreza Ahmadian1, William Ju2,4, Lidong Liu2,4, Michael Wyszynski3, Sang Hyoung Lee3, Anthone W Dunah3, Changiz Taghibiglou4, Yushan Wang4, Jie Lu4, Tak Pan Wong4, Morgan Sheng3 and Yu Tian Wang2,4

  1. National Research Center for Genetic Engineering and Biotechnology, Tehran, Iran
  2. Programme in Brain and Behaviour, Hospital for Sick Children and Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Canada
  3. Center for Learning and Memory and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
  4. Department of Medicine & Brain Research Centre, Vancouver Hospital & Health Sciences Centre, University of British Columbia, Vancouver, Canada

Correspondence to:

Yu Tian Wang, Department of Medicine & Brain Research Centre, Vancouver Hospital & Health Sciences Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5. Tel.: +1 604 822 0398; Fax: +1 604 822 7299; E-mail: ytwang@interchange.ubc.ca

Received 25 July 2003; Accepted 23 January 2004

The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors is subject to functionally distinct constitutive and regulated clathrin-dependent endocytosis, contributing to various forms of synaptic plasticity. In HEK293 cells transiently expressing GluR1 or GluR2 mutants containing domain deletions or point mutations in their intracellular carboxyl termini (CT), we found that deletion of the first 10 amino acids (834–843) selectively reduced the rate of constitutive AMPA receptor endocytosis, whereas truncation of the last 15 amino acids of the GluR2 CT, or point mutation of the tyrosine residues in this region, only eliminated the regulated (insulin-stimulated) endocytosis. Moreover, in hippocampal slices, both insulin treatment and low-frequency stimulation (LFS) specifically stimulated tyrosine phosphorylation of the GluR2 subunits of native AMPA receptors, and the enhanced phosphorylation appears necessary for both insulin- and LFS-induced long-term depression of AMPA receptor-mediated excitatory postsynaptic currents. Thus, our results demonstrate that constitutive and regulated AMPA receptor endocytosis requires different sequences within GluR CTs and tyrosine phosphorylation of GluR2 CT is required for the regulated AMPA receptor endocytosis and hence the expression of certain forms of synaptic plasticity.

  • Keywords:

    • AMPA receptor,
    • endocytosis,
    • hippocampal slices,
    • LTP,
    • tyrosine phosphorylation