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

46 Citations (Scopus)

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

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Serine
Neuroglia
Glutamic Acid
Type C Phospholipases
Metabotropic Glutamate Receptors
Membranes
Glutamate Receptors
N-Methylaspartate
Phosphatidylinositols
serine racemase

All Science Journal Classification (ASJC) codes

  • General

Cite this

Mustafa, Asif K. ; Van Rossum, Damian B. ; Patterson, Randen L. ; Maag, David ; Ehmsen, Jeffrey T. ; Gazi, Sadia K. ; Chakraborty, Anutosh ; Barrow, Roxanne K. ; Amzel, L. Mario ; Snyder, Solomon H. / Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 8. pp. 2921-2926.
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Mustafa, AK, Van Rossum, DB, Patterson, RL, Maag, D, Ehmsen, JT, Gazi, SK, Chakraborty, A, Barrow, RK, Amzel, LM & Snyder, SH 2009, 'Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 8, pp. 2921-2926. https://doi.org/10.1073/pnas.0813105106

Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition. / Mustafa, Asif K.; Van Rossum, Damian B.; Patterson, Randen L.; Maag, David; Ehmsen, Jeffrey T.; Gazi, Sadia K.; Chakraborty, Anutosh; Barrow, Roxanne K.; Amzel, L. Mario; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 8, 24.02.2009, p. 2921-2926.

Research output: Contribution to journalArticle

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T1 - Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition

AU - Mustafa, Asif K.

AU - Van Rossum, Damian B.

AU - Patterson, Randen L.

AU - Maag, David

AU - Ehmsen, Jeffrey T.

AU - Gazi, Sadia K.

AU - Chakraborty, Anutosh

AU - Barrow, Roxanne K.

AU - Amzel, L. Mario

AU - Snyder, Solomon H.

PY - 2009/2/24

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AB - 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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