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PNAS 102 (6): 2105-2110

Copyright © 2005 by the National Academy of Sciences.

NEUROSCIENCE

Serine racemase: Activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration

Paul M. Kim *, Hiroyuki Aizawa {dagger}, Peter S. Kim *, Alex S. Huang {dagger}, Sasrutha R. Wickramasinghe {dagger}, Amir H. Kashani {dagger}, Roxanne K. Barrow {dagger}, Richard L. Huganir {dagger}, {ddagger}, Anirvan Ghosh {dagger} §, and Solomon H. Snyder *, {dagger}, ¶, || **

Department of *Pharmacology and Molecular Science, {dagger}Neuroscience, and ||Psychiatry and Behavioral Sciences and {ddagger}Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Contributed by Solomon H. Snyder, December 28, 2004

Abstract: Serine racemase (SR), localized to astrocytic glia that ensheathe synapses, converts L-serine to D-serine, an endogenous ligand of the NMDA receptor. We report the activation of SR by glutamate neurotransmission involving {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors via glutamate receptor interacting protein (GRIP) and the physiologic regulation of cerebellar granule cell migration by SR. GRIP physiologically binds SR, augmenting SR activity and D-serine release. GRIP infection of neonatal mouse cerebellum in vivo enhances granule cell migration. Selective degradation of D-serine by D-amino acid oxidase and pharmacologic inhibition of SR impede migration, whereas D-serine activates the process. Thus, in neuronal migration, glutamate stimulates Bergmann glia to form and release D-serine, which, together with glutamate, activates NMDA receptors on granule neurons, chemokinetically enhancing migration.

Key Words: {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor • D-serine

Author contributions: P.M.K. and S.H.S. designed research; P.M.K., H.A., P.S.K., A.S.H., S.R.W., A.H.K., and R.K.B. performed research; P.M.K., H.A., R.L.H., A.G., and S.H.S. analyzed data; R.L.H. and A.G. contributed new reagents/analytic tools; and P.M.K. and S.H.S. wrote the paper.

Abbreviations: GRIP, glutamate receptor interacting protein; AMPA, {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; SR, serine racemase; DAO, D-amino acid oxidase; EGL, external granule layer; IGL, internal granule layer; ML, molecular layer; HEK, human embryonic kidney; GFAP, glial fibrillary acidic protein; NBQX, 6-nitro-7-sulfamoylbenzo(F)quinoxaline-2,3-dione; Pn, postnatal day n; RT, room temperature; Phen, phenazine; Et-Phen, phenazine ethosulfate; Met-Phen, phenazine methosulfate.

§ Present address: Division of Biology, University of California at San Diego, 1123 A Pacific Hall, 9500 Gilman Drive, La Jolla, CA 92093-0366.

** Patents related to this work have been licensed to Guilford Pharmaceuticals, of which S.H.S. is a director and consultant. S.H.S. and Johns Hopkins University are entitled to receive royalties from product sales. This matter is being handled by the Johns Hopkins Committee on Conflict of Interest in accordance with its policies.

To whom correspondence should be addressed. E-mail: ssnyder{at}jhmi.edu.

© 2005 by The National Academy of Sciences of the USA

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