Regulation of AMPA receptor trafficking and function by glycogen synthase kinase 3.
Accumulating evidence suggests that glycogen synthase kinase 3 (GSK-3) is a multifunctional kinase implicated in neuronal development, mood stabilization, and neurodegeneration. However, the synaptic actions of GSK-3 are largely unknown. In this study, we examined the impact of GSK-3 on AMPA receptor (AMPAR) channels, the major mediator of excitatory transmission, in cortical neurons. Application of GSK-3 inhibitors or knockdown of GSK-3 caused a significant reduction of the amplitude of miniature excitatory postsynaptic current (mEPSC), a readout of the unitary strength of synaptic AMPARs. Treatment with GSK-3 inhibitors also decreased surface and synaptic GluR1 clusters on dendrites and increased internalized GluR1 in cortical cultures. Rab5, the small GTPase controlling the transport from plasma membrane to early endosomes, was activated by GSK-3 inhibitors. Knockdown of Rab5 prevented GSK-3 inhibitors from regulating mEPSC amplitude. Guanyl nucleotide dissociation inhibitor (GDI), which regulates the cycle of Rab5 between membrane and cytosol, formed an increased complex with Rab5 after treatment with GSK-3 inhibitors. Blocking the function of GDI occluded the effect of GSK-3 inhibitors on mEPSC amplitude. In cells transfected with the non-phosphorylatable GDI mutant, GDI(S45A), GSK-3 inhibitors lost the capability to regulate GDI-Rab5 complex, mEPSC amplitude, and AMPAR surface expression. These results suggest that GSK-3, via altering the GDI-Rab5 complex, regulates Rab5-mediated endocytosis of AMPARs. It provides a potential mechanism underlying the role of GSK-3 in synaptic transmission and plasticity.
Wei
Jing
J
Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing 210009, Jiangsu Province, China. jwei83@yahoo.com.cn
Liu
Wenhua
W
Yan
Zhen
Z
D000818:Animals; D004705:Endocytosis; D019706:Excitatory Postsynaptic Potentials; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D009473:Neuronal Plasticity; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D009435:Synaptic Transmission; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D020730:Guanine Nucleotide Dissociation Inhibitors; D018091:Receptors, AMPA; D038362:Glycogen Synthase Kinase 3; D020696:rab5 GTP-Binding Proteins