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

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.

Author information

1
From The Solomon H. Snyder Department of Neuroscience and.
2
Departments of Pharmacology and Molecular Sciences and.
3
the Department of Biochemistry, Technion-Israel Institute of Technology, Haifa 31096, Israel.
4
From The Solomon H. Snyder Department of Neuroscience and Departments of Pharmacology and Molecular Sciences and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and ssnyder@jhmi.edu.

Abstract

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

PMID:
25164819
PMCID:
PMC4207978
DOI:
10.1074/jbc.M114.571604
[Indexed for MEDLINE]
Free PMC Article

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