Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition

Asif K. Mustafa, Damian B. Van Rossum, Randen L. Patterson, David Maag, Jeffrey T. Ehmsen, Sadia K. Gazi, Anutosh Chakraborty, Roxanne K. Barrow, L. Mario Amzel, Solomon H. Snyder

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2921-2926
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number8
DOIs
StatePublished - Feb 24 2009
Externally publishedYes

Keywords

  • D-serine
  • Metabotropic glutamate receptor
  • NMDA transmission
  • Phosphatidylinositol (4,5)-bisphosphate

ASJC Scopus subject areas

  • General

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    Mustafa, A. K., Van Rossum, D. B., Patterson, R. L., Maag, D., Ehmsen, J. T., Gazi, S. K., Chakraborty, A., Barrow, R. K., Amzel, L. M., & Snyder, S. H. (2009). Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2921-2926. https://doi.org/10.1073/pnas.0813105106