Churn S B, Limbrick D, Sombati S, DeLorenzo R J
Department of Neurology, Medical College of Virginia, Richmond 23298, USA.
J Neurosci. 1995 Apr;15(4):3200-14. doi: 10.1523/JNEUROSCI.15-04-03200.1995.
Neurotoxic effects of excitatory amino acids have been implicated in various neurological disorders, and have been utilized for excitotoxic models of delayed neuronal cell death. The excitotoxic glutamate-induced, delayed neuronal cell death also results in inhibition of calcium/calmodulin-dependent kinase II (CaM kinase II). In this report, we characterized the glutamate-induced inhibition of CaM kinase II in relation to loss of intracellular calcium regulation and delayed neuronal cell death. Glutamate (500 microM for 10 min), but not KCl (50 mM), exposure resulted in a significant inhibition of CaM kinase II activity. The inhibition of CaM kinase II activity was observed immediately following excitotoxic glutamate exposure and present at every time point measured. Glutamate-induced inhibition of kinase activity and delayed neuronal cell death was dependent upon both the activation of the NMDA glutamate 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 conditions which resulted in significant neuronal cell death and inhibition of CaM kinase II activity also resulted in a long-term loss of intracellular calcium regulation. Thus, inhibition of CaM kinase II activity occurred under experimental conditions which resulted in loss of neuronal viability and loss of neuronal calcium regulation. Since the glutamate-induced inhibition of CaM kinase II activity preceded neuronal cell death, the data support the hypothesis that inhibition of CaM kinase II activity may play a significant role in excitotoxicity-dependent, delayed neuronal cell death.
兴奋性氨基酸的神经毒性作用已被认为与多种神经系统疾病有关，并已被用于延迟性神经元细胞死亡的兴奋毒性模型。兴奋性毒性谷氨酸诱导的延迟性神经元细胞死亡也会导致钙/钙调蛋白依赖性激酶II（CaM激酶II）的抑制。在本报告中，我们描述了谷氨酸诱导的CaM激酶II抑制与细胞内钙调节丧失和延迟性神经元细胞死亡的关系。谷氨酸（500微摩尔，作用10分钟）而非氯化钾（50毫摩尔）的暴露导致CaM激酶II活性显著抑制。在兴奋性毒性谷氨酸暴露后立即观察到CaM激酶II活性的抑制，并且在测量的每个时间点都存在。谷氨酸诱导的激酶活性抑制和延迟性神经元细胞死亡既依赖于NMDA谷氨酸受体亚型的激活，也依赖于细胞外钙的存在。还研究了CaM激酶II活性抑制与细胞内钙调节丧失之间的关系。导致显著神经元细胞死亡和CaM激酶II活性抑制的实验条件也导致了细胞内钙调节的长期丧失。因此，在导致神经元活力丧失和神经元钙调节丧失的实验条件下发生了CaM激酶II活性的抑制。由于谷氨酸诱导的CaM激酶II活性抑制先于神经元细胞死亡，这些数据支持了以下假设：CaM激酶II活性的抑制可能在兴奋性毒性依赖性延迟性神经元细胞死亡中起重要作用。
