Glycogen synthase kinase 3 regulates N-methyl-D-aspartate receptor channel trafficking and function in cortical neurons.
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 N-methyl-D-aspartate (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-3beta in neuronal cultures with a small interfering RNA led to smaller NMDA receptor 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 kinesin superfamily member 17-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.
Chen
Paul
P
Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214, USA.
Gu
Zhenglin
Z
Liu
Wenhua
W
Yan
Zhen
Z
D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002966:Clathrin / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D004705:Endocytosis; D005625:Frontal Lobe / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016547:Kinesins / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D020696:rab5 GTP-Binding Proteins / Q000502:physiology
D002966:Clathrin; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins; D020696:rab5 GTP-Binding Proteins