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首页> 外文期刊>The European Journal of Neuroscience >Tissue-type plasminogen activator-plasmin-BDNF modulate glutamate-induced phase-shifts of the mouse suprachiasmatic circadian clock in vitro.
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Tissue-type plasminogen activator-plasmin-BDNF modulate glutamate-induced phase-shifts of the mouse suprachiasmatic circadian clock in vitro.

机译：组织型纤溶酶原激活物-纤溶酶-BDNF在体外调节谷氨酸诱导的小鼠超视交叉生物钟的相移。

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摘要

The mammalian circadian clock in the suprachiasmatic nucleus (SCN) maintains environmental synchrony through light signals transmitted by glutamate released from retinal ganglion terminals. Brain-derived neurotrophic factor (BDNF) is required for light/glutamate to reset the clock. In the hippocampus, BDNF is activated by the extracellular protease, plasmin, which is produced from plasminogen by tissue-type plasminogen activator (tPA). We provide data showing expression of proteins from the plasminogen activation cascade in the SCN and their involvement in circadian clock phase-resetting. Early night glutamate application to SCN-containing brain slices resets the circadian clock. Plasminogen activator inhibitor-1 (PAI-1) blocked these shifts in slices from wild-type mice but not mice lacking its stabilizing protein, vitronectin (VN). Plasmin, but not plasminogen, prevented inhibition by PAI-1. Both plasmin and active BDNF reversed alpha(2)-antiplasmin inhibition of glutamate-induced shifts. alpha(2)-Antiplasmin decreased the conversion of inactive to active BDNF in the SCN. Finally, both tPA and BDNF allowed daytime glutamate-induced phase-resetting. Together, these data are the first to demonstrate expression of these proteases in the SCN, their involvement in modulating photic phase-shifts, and their activation of BDNF in the SCN, a potential 'gating' mechanism for photic phase-resetting. These data also demonstrate a functional interaction between PAI-1 and VN in adult brain. Given the usual association of these proteins with the extracellular matrix, these data suggest new lines of investigation into the locations and processes modulating mammalian circadian clock phase-resetting.
机译：视交叉上核（SCN）中的哺乳动物生物钟通过从视网膜神经节末端释放的谷氨酸传递的光信号维持环境同步。光/谷氨酸重置时钟需要大脑衍生的神经营养因子（BDNF）。在海马中，BDNF被细胞外蛋白酶纤溶酶激活，纤溶酶由纤溶酶原通过组织型纤溶酶原激活剂（tPA）产生。我们提供的数据显示了SCN中来自纤溶酶原激活级联的蛋白质表达及其在昼夜节律相位重置中的参与。在含有SCN的脑切片上应用夜光谷氨酸可重置生物钟。纤溶酶原激活物抑制剂1（PAI-1）阻止了野生型小鼠切片中的这些转变，但没有缺乏其稳定蛋白玻连蛋白（Vnnectin）（VN）的小鼠。纤溶酶（但不是纤溶酶原）阻止了PAI-1的抑制作用。纤溶酶和活性BDNF都逆转了谷氨酸诱导的转变的alpha（2）-antiplasmin抑制。 alpha（2）-Antiplasmin减少了SCN中非活性BDNF的转化。最后，tPA和BDNF都允许白天谷氨酸诱导的相重置。总之，这些数据是第一个证明这些蛋白酶在SCN中的表达，它们参与调节光相转变以及它们在SCN中对BDNF的活化的一种数据，这是光相重置的潜在“门控”机制。这些数据还证明了成年大脑中PAI-1和VN之间的功能相互作用。考虑到这些蛋白质通常与细胞外基质相关联，这些数据暗示了研究哺乳动物昼夜节律相位重置的位置和过程的新方法。

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