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(Received for publication, September 10, 1996, and in revised form, February 21, 1997)
From the Department of Pharmacology, University of Wisconsin,
Madison, Wisconsin 53706-1532
Ca2+ influx through
N-methyl-D-aspartate (NMDA)-type glutamate
receptors plays a pivotal role in synaptic plasticity during brain
development as well as in mature brain. Cyclic
AMP-dependent protein kinase (PKA) and members of the
protein kinase C (PKC) family are also essential for various forms of
synaptic plasticity and regulate the activity of different ion channels
including NMDA and non-NMDA receptors. We now demonstrate that PKA and
various PKC isoforms phosphorylate the NMDA receptor in
vitro. The stoichiometry of [32P]phosphate
incorporation per [3H]MK-801 binding site is greater than
1 for both PKA and PKC. Double immunoprecipitation experiments show
that all three NMDA receptor subunits that are prevalent in the
cortical structures, NR1, NR2A, and NR2B, are substrates for PKA as
well as PKC. Two-dimensional phosphopeptide mapping reveals that the
major phosphorylation sites for PKA and PKC differ for all three
subunits. We provide evidence that some if not most of these sites are
phosphorylated in the central nervous system of rats in
vivo. The results presented in this article together with earlier
electrophysiological experiments demonstrating that PKA and PKC
activation increases the activity of NMDA receptors indicate that NMDA
receptor potentiation can be mediated by direct phosphorylation by PKA
and PKC. Collectively, these results strongly suggest that NMDA
receptor functions such as control of neuronal development or
expression of synaptic plasticity are modulated by PKA- and
PKC-mediated phosphorylation of NMDA receptors.
Volume 272, Number 18,
Issue of May 2, 1997
pp. 12107-12115
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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B.-S. Li, M.-K. Sun, L. Zhang, S. Takahashi, W. Ma, L. Vinade, A. B. Kulkarni, R. O. Brady, and H. C. Pant From the Cover: Regulation of NMDA receptors by cyclin-dependent kinase-5 PNAS, October 23, 2001; 98(22): 12742 - 12747. [Abstract] [Full Text] [PDF]
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