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The Journal of Neuroscience, October 15, 2008, 28(42):10561-10566; doi:10.1523/JNEUROSCI.2666-08.2008

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Brief Communications
The Tyrosine Phosphatase STEP Mediates AMPA Receptor Endocytosis after Metabotropic Glutamate Receptor Stimulation

Yang Zhang,¹ Deepa V. Venkitaramani,¹ Clare M. Gladding,² Yongfang Zhang,¹ Pradeep Kurup,¹ Elek Molnar,² Graham L. Collingridge,² and Paul J. Lombroso¹

¹Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, and ²Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom

Correspondence should be addressed to Dr. Paul J. Lombroso, Child Study Center, SHM I-270, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520. Email: paul.lombroso{at}yale.edu

Although it is well established that AMPA receptor (AMPAR) trafficking is a central event in several forms of synaptic plasticity, the mechanisms that regulate the surface expression of AMPARs are poorly understood. Previous work has shown that striatal-enriched protein tyrosine phosphatase (STEP) mediates NMDAR endocytosis. This protein tyrosine phosphatase is enriched in the synapses of the striatum, hippocampus, cerebral cortex, and other brain regions. In the present investigation, we have explored whether STEP also regulates AMPAR internalization. We found that (RS)-3,5-dihydroxyphenylglycine (DHPG) stimulation triggered a dose-dependent increase in STEP translation in hippocampal slices and synaptoneurosomes, a process that requires stimulation of mGluR5 (metabotropic glutamate receptor 5) and activation of mitogen-activated protein kinases and phosphoinositide-3 kinase pathways. DHPG-induced AMPAR internalization and tyrosine dephosphorylation of GluR2 (glutamate receptor 2) was blocked by a substrate-trapping TAT-STEP [C/S] protein in hippocampal slices and cultures. Moreover, DHPG-triggered AMPAR internalization was abolished in STEP knock-out mice and restored after replacement of wild-type STEP. These results suggest a role for STEP in the regulation of AMPAR trafficking.

Key words: protein tyrosine phosphatase; STEP; AMPA receptor trafficking; metabotropic glutamate receptor; protein synthesis; ERK1/2

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Received June 9, 2008; revised July 31, 2008; accepted Sept. 2, 2008.

Correspondence should be addressed to Dr. Paul J. Lombroso, Child Study Center, SHM I-270, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520. Email: paul.lombroso{at}yale.edu

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