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PNAS 98 (22): 12742-12747

Copyright © 2001 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / NEUROBIOLOGY

Regulation of NMDA receptors by cyclin-dependent kinase-5

Bing-Sheng Li*, Miao-Kun Sun{dagger}, Lei Zhang{ddagger}, Satoru Takahashi§, Wu Ma, Lucia Vinade||, Ashok B. Kulkarni§, Roscoe O. Brady**, and Harish C. Pant*,{ddagger}{ddagger}

*Laboratory of Neurochemistry, {dagger}Laboratory of Adaptive Systems, and ||Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; {ddagger}Behavioral Endocrinology Branch, National Institute of Mental Health, and §Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Washington, D.C. 20375; and **Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Contributed by Roscoe O. Brady

Accepted for publication August 14, 2001.

Abstract: Members of the N-methyl-D-aspartate (NMDA) class of glutamate receptors (NMDARs) are critical for development, synaptic transmission, learning and memory; they are targets of pathological disorders in the central nervous system. NMDARs are phosphorylated by both serine/threonine and tyrosine kinases. Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDA-evoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs.

{ddagger}{ddagger} To whom reprint requests should be addressed at: Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg 36, Rm 4D24, 9000 Rockville Pike, Bethesda, MD 20892-4130. E-mail: panth{at}ninds.nih.gov.

See commentary on page 12323.

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