Neuron-derived D-serine Release Provides a Novel Means to Activate N-methyl-d-aspartate Receptors.
From: Department of Biochemistry, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
The Journal of biological chemistry
- Publish Date: May 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 20
- Pages: 14151-62
- Medium: Print
- Language: English
- Citation (JAMA): Kartvelishvily Elena, Shleper Maria, Balan Livia, et al. Neuron-derived D-serine Release Provides a Novel Means to Activate N-methyl-d-aspartate Receptors.. J. Biol. Chem. May 2006;281:14151-62
Abstract
D-serine is a coagonist of N-methyl-D-aspartate (NMDA) receptors that occurs at high levels in the brain. Biosynthesis of D-serine is carried out by serine racemase, which converts L- to D-serine. D-serine has been demonstrated to occur in glial cells, leading to the proposal that astrocytes are the only source of D-serine. We now report significant amounts of serine racemase and D-serine in primary neuronal cultures and neurons in vivo. Several neuronal culture types expressed serine racemase, and D-serine synthesis was comparable with that in glial cultures. Immunohistochemical staining of brain sections with new antibodies revealed the presence of serine racemase and D-serine in neurons. Cortical neurons expressing serine racemase also expressed the NR2a subunit in situ. Neuron-derived D-serine contributes to NMDA receptor activation in cortical neuronal cultures. Degradation of endogenous D-serine by addition of the recombinant enzyme D-serine deaminase diminished NMDA-elicited excitotoxicity. Release of neuronal D-serine was mediated by ionotropic glutamate receptor agonists such as NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainate. Removal of either external Ca2+ or Na+ blocked D-serine release. Release of D-serine was mostly through a cytosolic route because it was insensitive to bafilomycin A1, a potent inhibitor of vesicular neurotransmitter uptake. D-serine was also not transported into purified synaptic vesicles under conditions optimal for the uptake of known transmitters. Our results suggest that neurons are a major source of D-serine. Glutamate-induced neuronal D-serine release provides a novel mechanism for activating NMDA receptors by an autocrine or paracrine way.
Mesh Headings (Keywords): Animals, Astrocytes, Brain, Cells, Cultured, Cytosol, Kainic Acid, Neurons, Propionic Acids, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Serine, Synapses
Check for Full Text / PubMed Unique Identifier (PMID): 16551623
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