Urokinase-type plasminogen activator modulates mammalian circadian clock phase regulation in tissue-type plasminogen activator knockout mice
Urokinase-type plasminogen activator modulates mammalian circadian clock phase regulation in tissue-type plasminogen activator knockout mice
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DOI：
10.1111/ejn.13511
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发表时间：
2017-03-01
影响因子：
3.4
通讯作者：
Prosser, Rebecca A.
中科院分区：
文献类型：
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作者：
Cooper, Joanna M.;Rastogi, Ashutosh;Prosser, Rebecca A.
谷氨酸通过激活NMDA受体改变哺乳动物视交叉上核（SCN）的生物钟。组织型纤溶酶原激活剂（tPA）通过激活纤溶酶产生m（ature）BDNF来门控相移，所述m（ature）BDNF结合TrkB受体以允许时钟相移。在这里，我们调查tPA敲除（tPA（-/-）; B6.129S2-Plat（tm 1 Mlg）/J）小鼠的相移，并确定尿激酶型纤溶酶原激活剂（uPA）作为一个额外的生物钟调节器。tPA（-/-）小鼠的行为活动节律诱导到一个亮-暗（LD）周期和相移，以响应夜间光脉冲，没有明显的灵敏度损失。当LD循环逆转时，tPA（-/-）小鼠比C57 BL/6 J野生型（WT）小鼠需要显著更长的时间来夹带。tPA（-/-）小鼠SCN脑切片显示出对夜间谷氨酸的响应的夹带神经元活动节律和相移，且无剂量依赖性变化。用tPA/uPA抑制剂、纤溶酶原激活物抑制剂-1（派-1）预处理切片可抑制tPA（-/-）切片中谷氨酸诱导的相位延迟。用UK 122选择性抑制uPA可防止tPA（-/-）切片中谷氨酸诱导的相位重置，但WT SCN切片不能。在WT SCN中，tPA表达在夜间高于白天，而uPA表达在WT和tPA（-/-）切片中保持恒定。酪蛋白-纤溶酶原酶谱显示，在WT或tPA（-/-）SCN中，tPA或uPA总蛋白水解活性均不受昼夜节律控制。最后，tPA（-/-）SCN组织比WT组织具有更低的mBDNF水平，而UK 122不影响任一品系中的mBDNF水平。总之，这些结果表明，无论是tPA或uPA可以支持SCN昼夜节律钟的光/光化学相移，可能通过不同的机制。
Glutamate phase shifts the circadian clock in the mammalian suprachiasmatic nucleus (SCN) by activating NMDA receptors. Tissue-type plasminogen activator (tPA) gates phase shifts by activating plasmin to generate m(ature) BDNF, which binds TrkB receptors allowing clock phase shifts. Here, we investigate phase shifting in tPA knockout (tPA(-/-); B6.129S2-Plat(tm1Mlg)/J) mice, and identify urokinase-type plasminogen activator (uPA) as an additional circadian clock regulator. Behavioral activity rhythms in tPA(-/-) mice entrain to a light-dark (LD) cycle and phase shift in response to nocturnal light pulses with no apparent loss in sensitivity. When the LD cycle is inverted, tPA(-/-) mice take significantly longer to entrain than C57BL/6J wild-type (WT) mice. SCN brain slices from tPA(-/-) mice exhibit entrained neuronal activity rhythms and phase shift in response to nocturnal glutamate with no change in dose-dependency. Pre-treating slices with the tPA/uPA inhibitor, plasminogen activator inhibitor-1 (PAI-1), inhibits glutamate-induced phase delays in tPA(-/-) slices. Selective inhibition of uPA with UK122 prevents glutamate-induced phase resetting in tPA(-/-) but not WT SCN slices. tPA expression is higher at night than the day in WT SCN, while uPA expression remains constant in WT and tPA(-/-) slices. Casein-plasminogen zymography reveals that neither tPA nor uPA total proteolytic activity is under circadian control in WT or tPA(-/-) SCN. Finally, tPA(-/-) SCN tissue has lower mBDNF levels than WT tissue, while UK122 does not affect mBDNF levels in either strain. Together, these results suggest that either tPA or uPA can support photic/glutamatergic phase shifts of the SCN circadian clock, possibly acting through distinct mechanisms.