Regulation of neuronal plasticity by calmodulin dependent protein phosphatase, Calcineurin

钙调蛋白依赖性蛋白磷酸酶、钙调磷酸酶调节神经元可塑性

基本信息

批准号：
08670053
负责人：
MATSUI Hideki
金额：
$ 1.47万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

The signals conveyed by intracellular Ca^<+2> ion concentration distribute into kinase system and phosphatase system, and express their physiological functions by controlling the phosphorylation level of target proteins. Calcineurin is a sole protein phosphatase which is directly regulated by Ca^<+2> and calmodulin and thus it is a key enzyme transmitting and amplifying signals by regulating serine/threonine phosphatase cascade. Calcineurin is extremely abundant in brain and co-localizes with FKBP12(FK506 binding protein 12) and cyclophilin(Cyclosporin A binding protein). Thus the immunosuppressants FK506 and Cyclosporin A(CysA) can specifically inhibits calcineurin activity.In this research project, we analysed the physiological role of calcineurin in central nervous system by the usage of FK506 and CysA as specific inhibitors. We specifically stressed the points as follows :1. The role of calcineurin in the control of synaptic plasticity of hippocampal neurons2. Calcineurin involvement in the acquisition of epileptogenesis induced by electrical kindling and morphological plasticity such as neuronal process extension and synaptogenesis observed in kindling.3. The role of calcineurin in the control mechanism of delayed neuronal cell death in hippocampal CA1 pyramidal neuron.4. The neuroprotection activity of FK506 in delayed neuronal cell death.We showed that calcineurin controls neuronal process formation, synaptogenesis and neuron network formation. The enzyme further controls the synapse plasticity such as LTP and LTD by modulating the NMDA channel and voltage -dependent calcium channel. Calcineurin has essential role in controlling the apoptosis of neurons and so the inhibitor of calcineurin, FK506 inhibits the neuronal apoptosis and works as neuro-protector.

细胞内Ca^+2离子浓度传递的信号分布到激酶系统和磷酸酶系统中，通过控制靶蛋白的磷酸化水平来表达其生理功能。钙调神经磷酸酶是唯一受Ca 2+ 和钙调蛋白直接调节的蛋白磷酸酶，因此它是通过调节丝氨酸/苏氨酸磷酸酶级联传递和放大信号的关键酶。钙调神经磷酸酶在大脑中极其丰富，并与 FKBP12（FK506 结合蛋白 12）和亲环蛋白（环孢菌素 A 结合蛋白）共定位。由此可见，免疫抑制剂FK506和环孢素A(CysA)可以特异性抑制钙调神经磷酸酶的活性。在本研究项目中，我们以FK506和CysA为特异性抑制剂，分析了钙调神经磷酸酶在中枢神经系统中的生理作用。我们特别强调以下几点： 1．钙调神经磷酸酶在控制海马神经元突触可塑性中的作用2。钙调神经磷酸酶参与电点燃诱导的癫痫发生和形态可塑性，如点燃中观察到的神经元过程延伸和突触发生。 3．钙调神经磷酸酶在海马CA1区锥体神经细胞迟发性细胞死亡控制机制中的作用。 4． FK506 在延迟神经元细胞死亡中的神经保护活性。我们发现钙调神经磷酸酶控制神经元过程形成、突触发生和神经元网络形成。该酶通过调节 NMDA 通道和电压依赖性钙通道进一步控制突触可塑性，如 LTP 和 LTD。钙调神经磷酸酶在控制神经元凋亡中具有重要作用，因此钙调神经磷酸酶抑制剂FK506可抑制神经元凋亡，起到神经保护剂的作用。