Glycine triggers a non-ionotropic activity of GluN2A-containing NMDA receptors to confer neuroprotection

Sci Rep. 2016 Oct 3:6:34459. doi: 10.1038/srep34459.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Female
  • Glycine / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*


  • Gprin1 protein, mouse
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Proto-Oncogene Proteins c-akt
  • Glycine
  • N-methyl D-aspartate receptor subtype 2A