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The Journal of Neuroscience, November 28, 2007, 27(48):13210-13221; doi:10.1523/JNEUROSCI.3056-07.2007

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Cellular/Molecular
NMDA Receptor Activation Dephosphorylates AMPA Receptor Glutamate Receptor 1 Subunits at Threonine 840

Jary Y. Delgado,¹ Marcelo Coba,⁵ Christopher N. G. Anderson,⁵ Kimberly R. Thompson,¹ Erin E. Gray,¹ Carrie L. Heusner,^2,3 Kelsey C. Martin,^2,3 Seth G. N. Grant,⁵ and Thomas J. O'Dell⁴

¹Interdepartmental PhD Program for Neuroscience, University of California, Los Angeles (UCLA), and Departments of ²Biological Chemistry, ³Psychiatry and Biobehavioral Sciences, and ⁴Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, and ⁵Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom

Correspondence should be addressed to Dr. Thomas J. O'Dell, Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, 53-231 Center for the Health Sciences, Box 951751, Los Angeles, CA 90095. Email: todell{at}mednet.ucla.edu

Phosphorylation-dependent changes in AMPA receptor function have a crucial role in activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Although three previously identified phosphorylation sites in AMPA receptor glutamate receptor 1 (GluR1) subunits (S818, S831, and S845) appear to have important roles in LTP and LTD, little is known about the role of other putative phosphorylation sites in GluR1. Here, we describe the characterization of a recently identified phosphorylation site in GluR1 at threonine 840. The results of in vivo and in vitro phosphorylation assays suggest that T840 is not a substrate for protein kinases known to phosphorylate GluR1 at previously identified phosphorylation sites, such as protein kinase A, protein kinase C, and calcium/calmodulin-dependent kinase II. Instead, in vitro phosphorylation assays suggest that T840 is a substrate for p70S6 kinase. Although LTP-inducing patterns of synaptic stimulation had no effect on GluR1 phosphorylation at T840 in the hippocampal CA1 region, bath application of NMDA induced a strong, protein phosphatase 1- and/or 2A-mediated decrease in T840 phosphorylation. Moreover, GluR1 phosphorylation at T840 was transiently decreased by a chemical LTD induction protocol that induced a short-term depression of synaptic strength and persistently decreased by a chemical LTD induction protocol that induced a lasting depression of synaptic transmission. Together, our results show that GluR1 phosphorylation at T840 is regulated by NMDA receptor activation and suggest that decreases in GluR1 phosphorylation at T840 may have a role in LTD.

Key words: AMPA receptor; GluR1; NMDA receptor; phosphorylation; long-term depression; hippocampus

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Received Oct. 22, 2006; revised Oct. 22, 2007; accepted Oct. 24, 2007.

Correspondence should be addressed to Dr. Thomas J. O'Dell, Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, 53-231 Center for the Health Sciences, Box 951751, Los Angeles, CA 90095. Email: todell{at}mednet.ucla.edu

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