cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock
cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock
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DOI：
10.1016/s0960-9822(03)00252-5
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发表时间：
2003-04-29
期刊：
影响因子：
9.2
通讯作者：
Albrecht, U
中科院分区：
文献类型：
--
作者：
Oster, H;Werner, C;Albrecht, U
背景：在哺乳动物中，驱动许多生化、生理和行为节律的生物钟位于下丘脑的视交叉上核(SCN)。昼夜节律性的产生和维持依赖于复杂的互锁转录/翻译反馈环，涉及一组时钟基因。在驱动哺乳动物生物钟的分子成分中，有周期1和2(mPer1和mPer2)基因。因为时钟的周期不是精确的24小时，所以它必须定期调整。调整(重置)时钟的主要刺激因素是夜间光线。它激活了SCN中的信号通路，最终导致mPer1和mPer2基因的表达，传递时钟的调节。结果：我们发现，尽管视网膜功能正常，但cGMP依赖的蛋白激酶II(cGKII，也称为PKGII)缺陷的小鼠在重新设置生物钟方面存在缺陷，这是通过光脉冲后车轮开始运行活动的变化来评估的。在分子水平上，cGKII缺陷小鼠SCN中mPer2的光诱导在夜间早期强烈降低，而mPer1的诱导在cGKII缺陷小鼠中升高。此外，在这些动物中，cGKII在时钟重置机制中起着一定的作用。特别是，cGKII缺陷小鼠延迟时钟相位的能力受到影响。似乎涉及cGKII的信号通路以相反的方式影响光诱导的mPer1和mPer2基因的诱导，从而影响生物钟的相移方向。
Background: In mammals, the master circadian clock that drives many biochemical, physiological, and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythmicity rely on complex interlocked transcriptional/translational feedback loops involving a set of clock genes. Among the molecular components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) genes. Because the periodicity of the clock is not exactly 24 hr, it has to be adjusted periodically. The major stimulus for adjustment (resetting) of the clock is nocturnal light. It evokes activation of signaling pathways in the SCN that ultimately lead to expression of mPer1 and mPer2 genes conveying adjustment of the clock.Results: We show that mice deficient in cGMP-dependent protein kinase II (cGKII, also known as PKGII), despite regular retinal function, are defective in resetting the circadian clock, as assessed by changes in the onset of wheel running activity after a light pulse. At the molecular level, light induction of mPer2 in the SCN is strongly reduced in the early period of the night, whereas mPer1 induction is elevated in cGKII-deficient mice. Additionally, we show that light induction of cfos and light-dependent phosphorylation of CREB at serine 133 are not affected in these animals.Conclusions: cGKII plays a role in the clock-resetting mechanism. In particular, the ability to delay clock phase is affected in cGKII-deficient mice. It seems that the signaling pathway involving cGKII influences in an opposite manner the light-induced induction of mPer1 and mPer2 genes and thereby influences the direction of a phase shift of the circadian clock.