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Molecular pharmacological studies on the expression of synaptic plasticity

突触可塑性表达的分子药理学研究

基本信息

批准号：
04670124
负责人：
FUKUNAGA Kohji
金额：
$ 1.34万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670124/
关键词：
Hippocampus Memory Learning Synaptic long-term potentiation Glutamate receptor NMDA receptor Ca^<2+> mobilization CaM kinase II 蛋白質燐酸化反応培養細胞

项目摘要

Long-term potentiation (LTP) is a form of synaptic plasticity widely investigated as a molecular basis of the memory formation. Studies on several protein kinase inhibitors have indicated a role of Ca^<2+>/calmodulin-dependent protein kinase II(CaM kinase II) in LTP of hippocampus. We hypothesized that elevation of intracellular Ca^<2+> through NMDA receptor activation would trigger autophosphorylation of CaM kinase II to form its Ca^<2+>-independent species, which would remain active even when the intracellular Ca^<2+> was resequestered to its basal level. In cultured hippocampal neurons, activation of NMDA receptor increased the Ca^<2+>-independent activity of CaM kinase II and in turn stimulated the phosphorylation of target proteins such as microtuble-associated protein 2 and synapsin I.Furthermore, high frequency stimulation applied to Cal afferents in the hippocampal slices resulted in the induction of LTP with concomitant long-lasting increases in the Ca^<2+>-independent and total CaM kinase II activities as well as an increases in the ratio of Ca^<2+>-independent to total activity. The effect was obtained using two different CaM kinase II substrates, syntide 2 and synapsin I, and it was observed in hippocampal slices and hippocampal organotypic cultures. The treatment of slices with NMDA receptor antagonist, D-2-amino-5-phosphonopentanoate prevent LTP induction and abolished the increase in the Ca^<2+>-independent activity as well as the increase in the total activity. These finding suggest that CaM kinase II can act as an important molecule for the formation of the hippocampal LTP.

长时程增强（LTP）是突触可塑性的一种形式，作为记忆形成的分子基础被广泛研究。对几种蛋白激酶抑制剂的研究表明，Ca^2+/钙调素依赖性蛋白激酶II（CaM激酶II）在海马LTP中的作用。我们假设，通过NMDA受体激活而升高的细胞内Ca^<2+>会触发CaM激酶II的自磷酸化，形成其Ca^<2+>非依赖性种类，即使细胞内Ca^<2+>重新分配到其基础水平，该种类仍将保持活性。在培养的海马神经元中，NMDA受体的激活增加了CaM激酶II的Ca^<2+>非依赖性活性，进而刺激了微管相关蛋白2和突触蛋白I等靶蛋白的磷酸化。高频刺激海马脑片中的Ca ~（2+）传入导致LTP的诱导，伴随着Ca^<2+>-独立的和总的CaM激酶II活性以及非Ca^2+依赖性与总活性的比率增加。使用两种不同的钙调蛋白激酶II底物，syntide 2和synapsin I，并在海马切片和海马器官型培养中观察到的效果。用NMDA受体拮抗剂D-2-amino-5-phosphonopentanoate处理脑片可阻止LTP的诱导，并消除Ca^2+非依赖性活性的增加以及总活性的增加。提示CaM激酶Ⅱ可能是海马LTP形成的重要分子。