TY - JOUR
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
Y1 - 2009/2/24
N2 - 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.
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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U2 - 10.1073/pnas.0813105106
DO - 10.1073/pnas.0813105106
M3 - Article
C2 - 19193859
AN - SCOPUS:62449236945
SN - 0027-8424
VL - 106
SP - 2921
EP - 2926
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -