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Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition

2009; National Academy of Sciences; Volume: 106; Issue: 8 Linguagem: Inglês

10.1073/pnas.0813105106

1091-6490

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,

Epigenetics and DNA Methylation

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.