title: Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition.
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.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Asif K
authors.initials: AK
authors.lastname: Mustafa
authors.forename: Damian B
authors.initials: DB
authors.lastname: van Rossum
authors.forename: Randen L
authors.initials: RL
authors.lastname: Patterson
authors.forename: David
authors.initials: D
authors.lastname: Maag
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Ehmsen
authors.forename: Sadia K
authors.initials: SK
authors.lastname: Gazi
authors.forename: Anutosh
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Barrow
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D005454:Fluorescence Polarization; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding; D019998:Racemases and Epimerases / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D000099300:Serine Racemase
chemical_list: D000255:Adenosine Triphosphate; D018698:Glutamic Acid; D019269:Phosphatidylinositol 4,5-Diphosphate; D019998:Racemases and Epimerases; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000099300:Serine Racemase; C578935:GRM5 protein, human