Serine Racemase Regulated by Binding to Stargazin and PSD-95: Potential NMDA-AMPA Glutamate Neurotransmission Cross-talk [Cell Biology]

August 27th, 2014 by Ma, T. M., Paul, B. D., Fu, C., Hu, S., Zhu, H., Blackshaw, S., Wolosker, H., Snyder, S. H.

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 de-repressing SR's 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.