Stimulatory effects of protein kinase C and calmodulin kinase II on N-methyl-D-aspartate receptor/channels in the postsynaptic density of rat brain.
To clarify the regulatory mechanism of the N-methyl-D-aspartate (NMDA) receptor/channel by several protein kinases, we examined the effects of purified type II of protein kinase C (PKC-II), endogenous Ca2+/calmodulin-dependent protein kinase II (CaMK-II), and purified cyclic AMP-dependent protein kinase on NMDA receptor/channel activity in the postsynaptic density (PSD) of rat brain. Purified PKC-II and endogenous CaMK-II catalyzed the phosphorylation of 80-200-kDa proteins in the PSD and L-glutamate- (or NMDA)-induced increase of (+)-5-[3H]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate ([3H]MK-801; open channel blocker for NMDA receptor/channel) binding activity was significantly enhanced. However, the pretreatment of PKC-II- and CaMK-II-catalyzed phosphorylation did not change the binding activity of L-[3H]glutamate, cis-4-[3H](phosphonomethyl)piperidine-2-carboxylate ([3H]CGS-19755; competitive NMDA receptor antagonist), [3H]glycine, alpha-[3H]-amino-3-hydroxy-5-methyl-isoxazole-4-propionate, or [3H]-kainate in the PSD. Pretreatment with PKC-II- and CaMK-II-catalyzed phosphorylation enhanced L-glutamate-induced increase of [3H]MK-801 binding additionally, although purified cyclic AMP-dependent protein kinase did not change L-glutamate-induced [3H]MK-801 binding. From these results, it is suggested that PKC-II and/or CaMK-II appears to induce the phosphorylation of the channel domain of the NMDA receptor/channel in the PSD and then cause an enhancement of Ca2+ influx through the channel.
Kitamura
Y
Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Miyazaki
A
A
Yamanaka
Y
Y
Nomura
Y
Y
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016291:Dizocilpine Maleate / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000494:pharmacology*; D011494:Protein Kinases / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000378:metabolism
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D011494:Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases