Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis.
Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis.
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DOI：
10.1523/jneurosci.4907-12.2013
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发表时间：
2013-03-06
期刊：
影响因子：
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通讯作者：
Baudry M
中科院分区：
文献类型：
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作者：
Briz V;Hsu YT;Li Y;Lee E;Bi X;Baudry M
记忆巩固被认为是蛋白质合成依赖性的。最近的数据表明，BDNF诱导的树突状蛋白的合成是通过激活哺乳动物雷帕霉素靶蛋白（mTOR）通路在记忆形成中的关键事件。BDNF还激活钙蛋白酶，一种钙依赖性半胱氨酸蛋白酶，已被证明在学习和记忆中发挥关键作用。因此，本研究旨在验证钙蛋白酶活性是BDNF刺激的局部蛋白质合成所需的假设，并确定潜在的分子机制。在大鼠海马脑片、皮质突触神经体和培养的神经元中，BDNF诱导的mTOR通路激活和蛋白翻译被钙蛋白酶抑制剂阻断。BDNF治疗以钙蛋白酶依赖性方式迅速降低了mTOR负调节因子hamartin和tuberin的水平。用纯化的钙蛋白酶-1和钙蛋白酶-2处理脑匀浆，两种蛋白质都被截短。BDNF处理增加Akt和ERK的磷酸化，但只有对Akt的作用被钙蛋白酶抑制剂阻断。PTEN（第十号染色体上缺失的磷酸酶和张力蛋白同源物）（一种使Akt失活的磷酸酶）的水平在BDNF治疗后降低，钙蛋白酶抑制剂逆转了这种作用。钙蛋白酶-2而不是钙蛋白酶-1处理脑匀浆导致PTEN降解。在培养的皮层神经元中，通过siRNA敲低calpain-2而不是calpain-1完全抑制了BDNF对mTOR激活的作用。我们的研究结果揭示了钙蛋白酶-2在BDNF诱导的mTOR信号转导和树突状蛋白合成中的关键作用，通过PTEN，hamartin和tuberin降解。因此，这种机制提供了蛋白质水解和蛋白质合成之间的联系，可能有助于突触可塑性。
Memory consolidation has been suggested to be protein synthesis-dependent. Recent data indicate that BDNF-induced dendritic protein synthesis is a key event in memory formation through activation of the mammalian target of rapamycin (mTOR) pathway. BDNF also activates calpain, a calcium-dependent cysteine protease, which has been shown to play a critical role in learning and memory. This study was therefore directed at testing the hypothesis that calpain activity is required for BDNF-stimulated local protein synthesis, and at identifying the underlying molecular mechanism. In rat hippocampal slices, cortical synaptoneurosomes, and cultured neurons, BDNF-induced mTOR pathway activation and protein translation were blocked by calpain inhibition. BDNF treatment rapidly reduced levels of hamartin and tuberin, negative regulators of mTOR, in a calpain-dependent manner. Treatment of brain homogenates with purified calpain-1 and calpain-2 truncated both proteins. BDNF treatment increased phosphorylation of both Akt and ERK, but only the effect on Akt was blocked by calpain inhibition. Levels of PTEN (phosphatase and tensin homolog deleted on chromosome ten), a phosphatase that inactivates Akt, were decreased following BDNF treatment, and calpain inhibition reversed this effect. Calpain-2 but not calpain-1 treatment of brain homogenates resulted in PTEN degradation. In cultured cortical neurons, knock-down of calpain-2 but not calpain-1 by siRNA completely suppressed the effect of BDNF on mTOR activation. Our results reveal a critical role for calpain-2 in BDNF-induced mTOR signaling and dendritic protein synthesis via PTEN, hamartin and tuberin degradation. This mechanism therefore provides a link between proteolysis and protein synthesis that might contribute to synaptic plasticity.