Serine racemase regulated by binding to stargazin and PSD-95: potential N-methyl-D-aspartate-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDA-AMPA) glutamate neurotransmission cross-talk

J Biol Chem. 2014 Oct 24;289(43):29631-41. doi: 10.1074/jbc.M114.571604. Epub 2014 Aug 27.


D-Serine, an endogenous co-agonist for the glycine site of the synaptic NMDA glutamate receptor, regulates synaptic plasticity and is implicated in schizophrenia. Serine racemase (SR) is the enzyme that converts L-serine to D-serine. In this study, we demonstrate that SR interacts with the synaptic proteins, postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. SR binds to the PDZ3 domain of PSD-95 through the PDZ domain ligand at its C terminus. SR also binds to the C terminus of stargazin, which facilitates the cell membrane localization of SR and inhibits its activity. AMPA receptor activation internalizes SR and disrupts its interaction with stargazin, therefore derepressing SR activity, leading to more D-serine production and potentially facilitating NMDA receptor activation. These interactions regulate the enzymatic activity as well as the intracellular localization of SR, potentially coupling the activities of NMDA and AMPA receptors. This shuttling of a neurotransmitter synthesizing enzyme between two receptors appears to be a novel mode of synaptic regulation.

Keywords: D-Serine; Enzyme; Ionotropic Glutamate Receptor; Neuron; Neurotransmitter; PSD-95; Stargazin; Synapse.

Publication types

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

MeSH terms

  • Animals
  • Biocatalysis
  • Calcium Channels / metabolism*
  • Cell Membrane / metabolism
  • Disks Large Homolog 4 Protein
  • Female
  • Glutamic Acid / metabolism*
  • Guanylate Kinases / metabolism*
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Models, Biological
  • N-Methylaspartate / metabolism*
  • Protein Binding
  • Racemases and Epimerases / metabolism*
  • Rats
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synaptic Transmission*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism*


  • Cacng2 protein, mouse
  • Calcium Channels
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Guanylate Kinases
  • Racemases and Epimerases
  • serine racemase