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(Received for publication, July 2, 1996, and in revised form, September 9, 1996)
From the Division of Biology, California Institute of Technology,
Pasadena, California 91125
The N-methyl-D-aspartate
(NMDA) subtype of excitatory glutamate receptors plays critical roles
in embryonic and adult synaptic plasticity in the central nervous
system. The receptor is a heteromultimer of core subunits, NR1, and one
or more regulatory subunits, NR2A-D. Protein phosphorylation can
regulate NMDA receptor function (Lieberman, D. N., and Mody, I. (1994)
Nature 369, 235-239; Wang, Y. T., and Salter, M. W. (1994)
Nature 369, 233-235; Wang, L.-Y., Orser, B. A., Brautigan,
D. L., and MacDonald, J. F. (1994) Nature 369, 230-232).
Here we identify a major phosphorylation site on subunit NR2B that is
phosphorylated by Ca2+/calmodulin-dependent
protein kinase II (CaM kinase II), an abundant protein kinase located
at postsynaptic sites in glutamatergic synapses. For the initial
identification of the site, we constructed a recombinant fusion protein
containing 334 amino acids of the C terminus of the NR2B subunit and
phosphorylated it with CaM kinase II in vitro. By peptide
mapping, automated sequencing, and mass spectrometry, we identified the
major site of phosphorylation on the fusion protein as Ser-383,
corresponding to Ser-1303 of full-length NR2B. The
Km for phosphorylation of this site in the fusion
protein was ~50 nM, much lower than that of other known
substrates for CaM kinase II, suggesting that the receptor is a high
affinity substrate. We show that serine 1303 in the full-length NR2B
and/or the cognate site in NR2A is a major site of phosphorylation of
the receptor both in the postsynaptic density fraction and in living
hippocampal neurons.
Volume 271, Number 49,
Issue of December 6, 1996
pp. 31670-31678
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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