Control of extracellular cleavage of ProBDNF by high frequency neuronal activity
Control of extracellular cleavage of ProBDNF by high frequency neuronal activity
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DOI：
10.1073/pnas.0807322106
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发表时间：
2009-01-27
影响因子：
11.1
通讯作者：
Lu, Bai
中科院分区：
文献类型：
--
作者：
Nagappan, Guhan;Zaitsev, Eugene;Lu, Bai
前和成熟的神经营养因子往往引起相反的生物学效应。例如，成熟的脑源性神经营养因子（mBDNF）对高频刺激诱导的长时程增强至关重要，而proBDNF促进低频刺激诱导的长时程抑郁。由于mBDNF是由原BDNF通过内切蛋白水解裂解而衍生的，因此调节原BDNF裂解的机制可能控制BDNF调节的方向。使用的方法，选择性地检测proBDNF或mBDNF，我们表明，低频刺激诱导培养的海马神经元主要proBDNF分泌。相反，高频刺激优先增加细胞外mBDNF。抑制细胞外，但不是细胞内的proBDNF裂解大大减少高频刺激诱导的细胞外mBDNF。此外，高频而非低频刺激选择性地诱导组织纤溶酶原激活物的分泌，组织纤溶酶原激活物是参与细胞外proBDNF向mBDNF转化的关键蛋白酶。因此，高频神经元活动通过调节细胞外蛋白酶的分泌来控制细胞外proBDNF/mBDNF的比率。我们的研究表明，分泌蛋白的细胞外蛋白水解裂解的活性依赖性控制，并揭示了一个重要的机制，控制截然相反的功能的BDNF亚型。
Pro-and mature neurotrophins often elicit opposing biological effects. For example, mature brain-derived neurotrophic factor (mBDNF) is critical for long-term potentiation induced by high-frequency stimulation, whereas proBDNF facilitate long-term depression induced by low-frequency stimulation. Because mBDNF is derived from proBDNF by endoproteolytic cleavage, mechanisms regulating the cleavage of proBDNF may control the direction of BDNF regulation. Using methods that selectively detect proBDNF or mBDNF, we show that low-frequency stimulation induced predominant proBDNF secretion in cultured hippocampal neurons. In contrast, high-frequency stimulation preferentially increased extracellular mBDNF. Inhibition of extracellular, but not intracellular cleavage of proBDNF greatly reduced high-frequency stimulation-induced extracellular mBDNF. Moreover, high-frequency, but not low-frequency stimulation selectively induced the secretion of tissue plasminogen activator, a key protease involved in extracellular proBDNF to mBDNF conversion. Thus, high-frequency neuronal activity controls the ratio of extracellular proBDNF/mBDNF by regulating the secretion of extracellular proteases. Our study demonstrates activity-dependent control of extracellular proteolytic cleavage of a secretory protein, and reveals an important mechanism that controls diametrically opposed functions of BDNF isoforms.