LIMBIC EPILEPSY IN TRANSGENIC MICE CARRYING A CA2+/CALMODULIN-DEPENDENT KINASE-II ALPHA-SUBUNIT MUTATION
LIMBIC EPILEPSY IN TRANSGENIC MICE CARRYING A CA2+/CALMODULIN-DEPENDENT KINASE-II ALPHA-SUBUNIT MUTATION
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DOI：
10.1073/pnas.92.15.6852
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发表时间：
1995-07-18
影响因子：
11.1
通讯作者：
MCNAMARA, JO
中科院分区：
文献类型：
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作者：
BUTLER, LS;SILVA, AJ;MCNAMARA, JO
多功能Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMK）磷酸化枢转地参与不同神经元过程的蛋白质，从而协调对调节细胞内Ca 2+的外部刺激的细胞应答[Hanson，P，I. Schulman，H.（1992）Annu. Rev.Biochem.61，559-664]，尽管进行了广泛的研究，但这种酶对哺乳动物神经系统中神经元群体兴奋性的原位控制的影响是未知的。为了解决这个问题，我们研究了转基因小鼠携带无效突变（-/-）的α亚基的钙调蛋白激酶。与野生型同窝仔相比，无效突变体表现出明显的过度兴奋性，在涉及边缘结构（包括海马）的癫痫发作中是明显的。在携带蛋白激酶C γ亚型无效突变的小鼠中未检测到兴奋性增加的证据，这强调了CaMK作用的特异性。在哺乳动物神经系统中，CaMK在控制神经元兴奋性方面起着强大而以前未被充分认识的作用。这些见解对癫痫机制的分析，也许，学习和记忆具有重要意义。
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. and 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 unknoull. 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.