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 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.
Mustafa
Asif K
AK
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
van Rossum
Damian B
DB
Patterson
Randen L
RL
Maag
David
D
Ehmsen
Jeffrey T
JT
Gazi
Sadia K
SK
Chakraborty
Anutosh
A
Barrow
Roxanne K
RK
Amzel
L Mario
LM
Snyder
Solomon H
SH
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
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