17-β-Estradiol increases neuronal excitability through MAP kinase-induced calpain activation
17-β-Estradiol increases neuronal excitability through MAP kinase-induced calpain activation
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DOI：
10.1073/pnas.0912558106
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发表时间：
2009-12-22
影响因子：
11.1
通讯作者：
Baudry, Michel
中科院分区：
文献类型：
--
作者：
Zadran, Sohila;Qin, Qingyu;Baudry, Michel
17-β-雌二醇（E2）是一种类固醇激素，参与许多大脑功能。E2通过增强海马中NMDA受体功能和棘密度来部分调节突触可塑性，从而导致学习和记忆的长时程增强和促进。由于钙依赖性中性蛋白酶，钙蛋白酶，也参与了这些过程，我们测试了E2是否可以激活钙蛋白酶，并研究了E2介导的钙蛋白酶激活海马的功能后果。钙蛋白酶活性分析的荧光共振能量转移（FRET）为基础的测定，允许定量测定和空间分辨率。E2迅速激活钙蛋白酶在培养的皮层和海马神经元，突出的树突和树突棘。E2诱导的钙蛋白酶激活是通过丝裂原活化蛋白激酶（MAPK）介导的，因为它完全被MEK抑制剂阻断。它也是钙非依赖性的，因为它在钙螯合剂BAPTA-AM存在下仍然很明显。通过特异性激动剂激活ER α和ER β受体刺激钙蛋白酶活性。最后，E2介导的急性海马脑片兴奋性的快速增加被膜渗透性钙蛋白酶抑制剂阻止。此外，E2治疗急性海马切片导致肌动蛋白聚合和膜水平的GluR 1，但不是GluR 2/3亚基的AMPA受体，这两种效果也被阻断钙蛋白酶抑制剂。我们的研究结果表明，E2通过MAP激酶介导的磷酸化迅速刺激钙蛋白酶活性，导致AMPA受体的膜水平增加。这些作用可能是负责E2介导的神经元兴奋性和促进认知过程的增加。
17-beta-Estradiol (E2) is a steroid hormone involved in numerous brain functions. E2 regulates synaptic plasticity in part by enhancing NMDA receptor function and spine density in the hippocampus, resulting in increased long-term potentiation and facilitation of learning and memory. As the calcium-dependent neutral protease, calpain, is also involved in these processes, we tested whether E2 could activate calpain and examined the functional consequences of E2-mediated calpain activation in hippocampus. Calpain activity was analyzed by a fluorescence resonance energy transfer (FRET)-based assay that allows both quantitative determination and spatial resolution. E2 rapidly activated calpain in cultured cortical and hippocampal neurons, prominently in dendrites and dendritic spines. E2-induced calpain activation was mediated through mitogen-activated protein kinase (MAPK), as it was completely blocked by MEK inhibitors. It was also calcium-independent, as it was still evident in presence of the calcium chelator, BAPTA-AM. Activation of ER alpha and ER beta receptors by specific agonists stimulated calpain activity. Finally, the rapid E2-mediated increase in excitability in acute hippocampal slices was prevented by a membrane-permeable calpain inhibitor. Furthermore, E2 treatment of acute hippocampal slices resulted in increased actin polymerization and membrane levels of GluR1 but not GluR2/3 subunits of AMPA receptors; both effects were also blocked by a calpain inhibitor. Our results indicate that E2 rapidly stimulates calpain activity through MAP kinase-mediated phosphorylation, resulting in increased membrane levels of AMPA receptors. These effects could be responsible for E2-mediated increase in neuronal excitability and facilitation of cognitive processes.