Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (8), p.2921-2926
Main Authors: Mustafa, Asif K, Rossum, Damian B. van, Patterson, Randen L, Maag, David, Ehmsen, Jeffrey T, Gazi, Sadia K, Chakraborty, Anutosh, Barrow, Roxanne K, Amzel, L. Mario, Snyder, Solomon H
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Anisotropy
Binding sites
Binding, Competitive
Biological Sciences
Cell Line
Cell membranes
Enzymes
Fluorescence
Fluorescence Polarization
Glutamic Acid - metabolism
HEK293 cells
Humans
Immunohistochemistry
Lipids
Membranes
Mutation
N methyl D aspartate receptors
Neuroglia
Neurons
Neurotransmission
Phosphatidylinositol 4,5-Diphosphate - antagonists & inhibitors
Phosphatidylinositol 4,5-Diphosphate - metabolism
Phospholipids
Protein Binding
Protein folding
Racemases and Epimerases - metabolism
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate - metabolism
Tissues
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0813105106