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First published on March 30, 2007; DOI: 10.1124/mol.107.034942

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Received for publication February 8, 2007.
Revised March 30, 2007.
Accepted for publication March 30, 2007.

Glycogen Synthase Kinase 3 Regulates NMDA Receptor Channel Trafficking and Function in Cortical Neurons

Paul Chen 1, Zhenglin Gu 1, Wenhua Liu 1, Zhen Yan 2*

1 SUNY at Buffalo 2 State University of New York at Buffalo

* Address correspondence to: E-mail: zhenyan{at}buffalo.edu

Abstract

Emerging evidence has suggested that glycogen synthase kinase 3 (GSK-3) is a key regulatory kinase involved in a plethora of processes in the nervous system including neuronal development, mood stabilization and neurodegeneration. However, the cellular mechanisms underlying the actions of GSK-3 remain to be identified. In this study, we examined the impact of GSK-3 on the NMDA receptor channel, a central player involved in cognitive and emotional processes. We found that application of various structurally different GSK-3 inhibitors caused a long-lasting reduction of NMDA receptor-mediated ionic and synaptic current in cortical pyramidal neurons. Cellular knockdown of GSK-3{beta} in neuronal cultures with a small interfering RNA led to smaller NMDAR current and loss of its regulation by GSK-3 inhibitors. The NR2B subunit-containing NMDA receptor was the primary target of GSK-3, but the GSK-3 modulation of NMDAR current did not involve the motor protein KIF17-based transport of NR2B-containing vesicles along microtubules. Combined electrophysiological, immunocytochemical and biochemical evidence indicated that GSK-3 inhibitors induced the down-regulation of NMDAR current through increasing the Rab5-mediated and PSD-95-regulated NMDAR internalization in a clathrin/dynamin-dependent manner.


Key words: Protein Kinases (other), Synaptic plasticity


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