Regulation of neuronal plasticity by calmodulin dependent protein phosphatase, Calcineurin

细胞内Ca~(2+)离子浓度传递的信号分布于激酶系统和磷酸系统，并通过控制靶蛋白的磷酸化水平来表达其生理功能。钙调神经磷酸酶是一种唯一的蛋白磷酸酶，受钙调素和钙调素的直接调节，是通过调节丝氨酸/苏氨酸磷酸酶级联反应来传递和放大信号的关键酶。钙调神经磷酸酶在脑中含量极其丰富，并与FKBP12(FK506结合蛋白12)和亲环素(环孢素A结合蛋白)共同定位。因此，免疫抑制剂FK506和环孢菌素A(Cyloporin A，CySA)可以特异性地抑制钙调神经磷酸酶的活性。在本研究中，我们利用FK506和CysA作为特异性抑制剂，分析了钙调神经磷酸酶在中枢神经系统中的生理作用。我们特别强调了以下几点：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钙调神经磷酸酶参与电点燃所致癫痫的获得性以及点燃时观察到的神经元突起延伸、突触形成等形态可塑性。钙调神经磷酸酶在海马CA1区锥体神经元迟发性神经元死亡调控机制中的作用。FK506在迟发性神经细胞死亡中的神经保护作用。我们发现钙调神经磷酸酶控制神经元突起的形成、突触的形成和神经元网络的形成。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的可塑性，如LTP和LTD。钙调神经磷酸酶在控制神经元的凋亡中具有重要作用，因此钙调神经磷酸酶抑制剂FK506抑制神经元的凋亡，起到神经保护的作用。

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.