EXCITOTOXIC ACTIVATION OF THE NMDA RECEPTOR RESULTS IN INHIBITION OF CALCIUM-CALMODULIN KINASE-II ACTIVITY IN CULTURED HIPPOCAMPAL-NEURONS

Neurotoxic effects of excitatory amino acids have been implicated in v arious neurological disorders, and have been utilized for excitotoxic models of delayed neuronal cell death, The excitotoxic glutamate-induc ed, delayed neuronal cell death also results in inhibition of calcium/ calmodulin-dependent kinase II (CaM kinase II), In this report, we cha racterized the glutamate-induced inhibition of CaM kinase II in relati on to loss of intracellular calcium regulation and delayed neuronal ce ll death. Glutamate (500 mu M for 10 min), but not KCI (50 mM), exposu re resulted in a significant inhibition of CaM kinase II activity, The inhibition of CaM kinase II activity was observed immediately followi ng excitotoxic glutamate exposure and present at every time point meas ured. Glutamate-induced inhibition of kinase activity and delayed neur onal cell death was dependent upon both the activation of the NMDA glu tamate receptor subtype and the presence of extracellular calcium, The relationship between inhibition of CaM kinase II activity and loss of intracellular calcium regulation was also examined, Experimental cond itions which resulted in significant neuronal cell death and inhibitio n of CaM kinase II activity also resulted in a long-term loss of intra cellular calcium regulation. Thus, inhibition of CaM kinase II activit y occurred under experimental conditions which resulted in loss of neu ronal viability and loss of neuronal calcium regulation. Since the glu tamate-induced inhibition of CaM kinase II activity preceded neuronal cell death, the data support the hypothesis that inhibition of CaM kin ase II activity may play a significant role in excitotoxicity-dependen t, delayed neuronal cell death.