Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 8, Pages 2921-2926Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0813105106
Keywords
D-serine; metabotropic glutamate receptor; NMDA transmission; phosphatidylinositol (4,5)-bisphosphate
Categories
Funding
- National Institutes of Health [1 F30 MH074191-01A2, MH18501, DA00074]
- Pennsylvania Department of Health
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0843282] Funding Source: National Science Foundation
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D-serine is a physiologic coagonist with glutamate at NMDA-subtype glutamate receptors. As D-serine is localized in glia, synaptically released glutamate presumably stimulates the glia to form and release D-serine, enabling glutamate/D-serine cotransmission. We show that serine racemase (SR), which generates D-serine from L-serine, is physiologically inhibited by phosphatidylinositol (4,5)-bisphosphate (PIP2) presence in membranes where SR is localized. Activation of metabotropic glutamate receptors (mGluR5) on glia leads to phospholipase C-mediated degradation of PIP2, relieving SR inhibition. Thus mutants of SR that cannot bind PIP2 lose their membrane localizations and display a 4-fold enhancement of catalytic activity. Moreover, mGluR5 activation of SR activity is abolished by inhibiting phospholipase C.
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