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The Journal of Neuroscience, October 1, 2000, 20(19):7258-7267
Phosphorylation of the AMPA Receptor Subunit GluR2 Differentially
Regulates Its Interaction with PDZ Domain-Containing Proteins
Hee Jung
Chung,
Jun
Xia,
Robert H.
Scannevin,
Xiaoqun
Zhang, and
Richard L.
Huganir
Department of Neuroscience, Howard Hughes Medical Institute, Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205
PSD-95, DLG, ZO-1 (PDZ) domain-mediated protein interactions
have been shown to play important roles in the regulation of glutamate
receptor function at excitatory synapses. Recent studies demonstrating
the rapid regulation of AMPA receptor function during synaptic
plasticity have suggested that AMPA receptor interaction with PDZ
domain-containing proteins may be dynamically modulated. Here we show
that PKC phosphorylation of the AMPA receptor GluR2 subunit
differentially modulates its interaction with the PDZ domain-containing
proteins GRIP1 and PICK1. The serine residue [serine-880 (Ser880)] in
the GluR2 C-terminal sequence (IESVKI) critical for PDZ
domain binding is a substrate of PKC and is phosphorylated in
vivo. In vitro binding and coimmunoprecipitation
studies show that phosphorylation of serine-880 within the GluR2 PDZ
ligand significantly decreases GluR2 binding to GRIP1 but not to PICK1. Immunostaining of cultured hippocampal neurons demonstrates that the
Ser880-phosphorylated GluR2 subunits are enriched and colocalized with
PICK1 in the dendrites, with very little staining observed at
excitatory synapses. Interestingly, PKC activation in neurons increases
the Ser880 phosphorylation of GluR2 subunits and recruits PICK1 to
excitatory synapses. Moreover, PKC stimulation in neurons results in
rapid internalization of surface GluR2 subunits. These results suggest
that GluR2 phosphorylation of serine-880 may be important in the
regulation of the AMPA receptor internalization during synaptic plasticity.
Key words:
GRIP1; PICK1; AMPA receptor; phosphorylation; PKC; PDZ
domain
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197258-10$05.00/0
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