PT  - JOURNAL ARTICLE
AU  - Wei-Yang Lu
AU  - Michael F. Jackson
AU  - Donglin Bai
AU  - Beverley A. Orser
AU  - John F. MacDonald
TI  - In CA1 Pyramidal Neurons of the Hippocampus Protein Kinase C Regulates Calcium-Dependent Inactivation of NMDA Receptors
AID  - 10.1523/JNEUROSCI.20-12-04452.2000
DP  - 2000 Jun 15
TA  - The Journal of Neuroscience
PG  - 4452--4461
VI  - 20
IP  - 12
4099  - http://www.jneurosci.org/content/20/12/4452.short
4100  - http://www.jneurosci.org/content/20/12/4452.full
SO  - J. Neurosci.2000 Jun 15; 20
AB  - 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 4β-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 enhancesIP via a sequential activation of the focal adhesion kinase cell adhesion kinase β/proline-rich tyrosine kinase 2 (CAKβ/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/CAKβ/Src-signaling pathway but depends on the concentration of extracellular Ca2+. Intracellular applications of CaM reducedIss/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 ofIss. 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.