Glycine triggers a non-ionotropic activity of GluN2A-containing NMDA receptors to confer neuroprotection.
Ionotropic activation of NMDA receptors (NMDARs) requires agonist glutamate and co-agonist glycine. Here we show that glycine enhances the activation of cell survival-promoting kinase Akt in cultured cortical neurons in which both the channel activity of NMDARs and the glycine receptors are pre-inhibited. The effect of glycine is reduced by shRNA-mediated knockdown of GluN2A subunit-containing NMDARs (GluN2ARs), suggesting that a non-ionotropic activity of GluN2ARs mediates glycine-induced Akt activation. In support of this finding, glycine enhances Akt activation in HEK293 cells over-expressing GluN2ARs. The effect of glycine on Akt activation is sensitive to the antagonist of glycine-GluN1 binding site. As a functional consequence, glycine protects against excitotoxicity-induced neuronal death through the non-ionotropic activity of GluN2ARs and the neuroprotective effect is attenuated by Akt inhibition. Thus, this study reveals an unexpected role of glycine in eliciting a non-ionotropic activity of GluN2ARs to confer neuroprotection via Akt activation.
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, Nevada, 89557, USA.|Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Rong
R
Hu
Department of Physiology, School of Basic Medical Sciences, Wuhan University School of Medicine, 185 Donghu Street, Wuhan 430071, China.|Department of Neurology, the Central Hospital of Wuhan, Wuhan 430060, China.
Juan
J
Chen
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, Nevada, 89557, USA.
Brendan
B
Lujan
Department of Physiology, School of Basic Medical Sciences, Wuhan University School of Medicine, 185 Donghu Street, Wuhan 430071, China.
Ruixue
R
Lei
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, Nevada, 89557, USA.
Mi
M
Zhang
Department of Physiology, School of Basic Medical Sciences, Wuhan University School of Medicine, 185 Donghu Street, Wuhan 430071, China.
Zefen
Z
Wang
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, Nevada, 89557, USA.
Mingxia
M
Liao
Department of Neurosurgery, Zhongnan Hospital, Wuhan University School of Medicine, 169 Donghu Street, Wuhan 430071, China.
Zhiqiang
Z
Li
Department of Physiology, School of Basic Medical Sciences, Wuhan University School of Medicine, 185 Donghu Street, Wuhan 430071, China.
Yu
Y
Wan
Campbell Research Institute, Centre for Addiction and Mental Health, and Departments of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8, Canada.
Fang
F
Liu
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Hua
H
Feng
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, Nevada, 89557, USA.|Department of Physiology, School of Basic Medical Sciences, Wuhan University School of Medicine, 185 Donghu Street, Wuhan 430071, China.|Department of Neurosurgery, Zhongnan Hospital, Wuhan University School of Medicine, 169 Donghu Street, Wuhan 430071, China.
Qi
Q
Wan
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005998:Glycine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D005998:Glycine; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D016194:Receptors, N-Methyl-D-Aspartate; C121673:Gprin1 protein, mouse
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