Butler L S, Silva A J, Abeliovich A, Watanabe Y, Tonegawa S, McNamara J O
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6852-5. doi: 10.1073/pnas.92.15.6852.
Multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMK) phosphorylates proteins pivotally involved in diverse neuronal processes and thereby coordinates cellular responses to external stimuli that regulate intracellular Ca2+ [Hanson, P. I. & Schulman, H. (1992) Annu. Rev. Biochem. 61, 559-664]. Despite extensive study, the impact of this enzyme on control of the excitability of neuron populations in the mammalian nervous system in situ is unknown. To address this question, we studied transgenic mice carrying a null mutation (-/-) for the alpha subunit of CaMK. In contrast to wild-type littermates, null mutants exhibit profound hyperexcitability, evident in epileptic seizures involving limbic structures including the hippocampus. No evidence of increased excitability was detected in mice carrying null mutations of the gamma isoform of protein kinase C, underscoring the specificity of the effect of CaMK. CaMK plays a powerful and previously underappreciated role in control of neuronal excitability in the mammalian nervous system. These insights have important implications for analyses of mechanisms of epilepsy and, perhaps, learning and memory.
多功能钙/钙调蛋白依赖性蛋白激酶II（CaMK）可磷酸化在多种神经元过程中起关键作用的蛋白质，从而协调细胞对调节细胞内钙离子的外部刺激的反应[汉森，P.I.和舒尔曼，H.（1992年）《生物化学年度评论》61卷，559 - 664页]。尽管进行了广泛研究，但该酶对哺乳动物神经系统中神经元群体兴奋性控制的影响尚不清楚。为了解决这个问题，我们研究了携带CaMKα亚基无效突变（-/-）的转基因小鼠。与野生型同窝小鼠相比，无效突变体表现出严重的过度兴奋，这在涉及包括海马体在内的边缘结构的癫痫发作中很明显。在携带蛋白激酶Cγ亚型无效突变的小鼠中未检测到兴奋性增加的证据，这突出了CaMK作用的特异性。CaMK在哺乳动物神经系统中对神经元兴奋性的控制中发挥着强大且此前未被充分认识的作用。这些见解对癫痫机制分析以及可能对学习和记忆的分析具有重要意义。
