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The Journal of Neuroscience, June 15, 2000, 20(12):4452-4461
In CA1 Pyramidal Neurons of the Hippocampus Protein Kinase C
Regulates Calcium-Dependent Inactivation of NMDA Receptors
Wei-Yang
Lu,
Michael F.
Jackson,
Donglin
Bai,
Beverley
A.
Orser, and
John F.
MacDonald
Departments of Physiology and Pharmacology, University of Toronto,
Toronto, Ontario M5S 1A8 Canada
The NMDA subtype of the glutamate-gated channel exhibits a
high permeability to Ca2+. The influx of
Ca2+ through NMDA channels is limited by a rapid and
Ca2+/calmodulin (CaM)-dependent inactivation that
results from a competitive displacement of cytoskeleton-binding
proteins from the NR1 subunit of the receptor by
Ca2+/CaM (Zhang et al., 1998; Krupp et al., 1999).
The C terminal of this subunit can be phosphorylated by protein kinase
C (PKC) (Tingley et al., 1993). The present study sought to investigate whether PKC regulates Ca2+-dependent inactivation of
the NMDA channel in hippocampal neurons. Activation of endogenous PKC
by 4 -phorbol 12-myristate 13-acetate enhanced peak
(Ip) and depressed steady-state
(Iss) NMDA-evoked currents, resulting
in a reduction in the ratio of these currents (Iss/Ip).
We demonstrated previously that PKC activity enhances IP via a sequential activation of the focal
adhesion kinase cell adhesion kinase /proline-rich tyrosine kinase 2 (CAK/Pyk2) and the nonreceptor tyrosine kinase Src (Huang et
al., 1999; Lu et al., 1999). Here, we report that the PKC-induced
depression of Iss is unrelated to the
PKC/CAK/Src-signaling pathway but depends on the concentration of
extracellular Ca2+. Intracellular applications of
CaM reduced
Iss/Ip and
occluded the Ca2+-dependent effect of phorbol esters
on Iss. Moreover, increasing the
concentration of intracellular Ca2+ buffer or
intracellular application of the inhibitory CaM-binding peptide
(KY9) greatly reduced the phorbol ester-induced depression of
Iss. Taken together, these results suggest
that PKC enhances Ca2+/CaM-dependent inactivation of
the NMDA channel, most likely because of a phosphorylation-dependent
regulation of interactions between receptor subunits, CaM, and other
postsynaptic density proteins.
Key words:
NMDA receptor; desensitization; Ca2+-dependent inactivation; calmodulin; PKC; phosphorylation; hippocampal neurons
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124452-10$05.00/0
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