A novel mechanism controlling resetting speed of the circadian clock to environmental stimuli.
A novel mechanism controlling resetting speed of the circadian clock to environmental stimuli.
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DOI：
10.1016/j.cub.2014.02.027
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发表时间：
2014-03-31
期刊：
影响因子：
9.2
通讯作者：
Bechtold, David A.
中科院分区：
文献类型：
--
作者：
Pilorz, Violetta;Cunningham, Peter S.;Jackson, Anthony;West, Alexander C.;Wager, Travis T.;Loudon, Andrew S. I.;Bechtold, David A.
哺乳动物生理学的许多方面都是通过内部生物钟的协调作用来驱动的。时钟速度（周期）和相位（时间对齐）是生物体与环境同步的基本能力。在人类中，打乱这些生物钟的生活方式，如轮班工作，会增加癌症和糖尿病等疾病的发病率。酪蛋白激酶1δ和ε是与周期确定密切相关的时钟组分。然而，CK 1 δ在这方面占据主导地位，因此尚不清楚CK 1 ε通常具有什么功能。在这里，我们揭示了CK 1 ε决定了环境刺激重置时钟的速度。小鼠中CK 1 ε的遗传破坏增强了行为节律对急性光脉冲的相位重置和光周期的转变。在NMDA或温度诱导的相移期间，CK 1 ε靶向的这种影响在与改变的PERIOD（PER）蛋白动力学相关的分离的脑视交叉上核和外周（肺）时钟中重现。重要的是，通过药理学抑制CK 1 ε，可以在野生型动物中实现体内和体外昼夜节律系统的加速再夹带。因此，这些研究揭示了CK 1 ε在稳定昼夜节律时钟对抗相移方面的作用，并强调它是最大限度地减少轮班工人生理干扰的新目标。CK 1 ε−/−小鼠对提前和延迟刺激表现出增强的相位重置PF 4800567对CK 1 ε的选择性药理学抑制增强重置在中枢和外周时钟中观察到加速重置加速重置减少生理学延迟Pilorz et al.揭示了CK 1 ε在稳定生物钟相位中的新作用。通过遗传和药理学靶向，他们证明了CK 1 ε决定了光（光）和非光（温度）刺激重置时钟的速度，从而突出了减少轮班工作中生理干扰的新目标。
Many aspects of mammalian physiology are driven through the coordinated action of internal circadian clocks. Clock speed (period) and phase (temporal alignment) are fundamental to an organism’s ability to synchronize with its environment. In humans, lifestyles that disturb these clocks, such as shift work, increase the incidence of diseases such as cancer and diabetes. Casein kinases 1δ and ε are closely related clock components implicated in period determination. However, CK1δ is so dominant in this regard that it remains unclear what function CK1ε normally serves. Here, we reveal that CK1ε dictates how rapidly the clock is reset by environmental stimuli. Genetic disruption of CK1ε in mice enhances phase resetting of behavioral rhythms to acute light pulses and shifts in light cycle. This impact of CK1ε targeting is recapitulated in isolated brain suprachiasmatic nucleus and peripheral (lung) clocks during NMDA- or temperature-induced phase shift in association with altered PERIOD (PER) protein dynamics. Importantly, accelerated re-entrainment of the circadian system in vivo and in vitro can be achieved in wild-type animals through pharmacological inhibition of CK1ε. These studies therefore reveal a role for CK1ε in stabilizing the circadian clock against phase shift and highlight it as a novel target for minimizing physiological disturbance in shift workers. CK1ε−/− mice exhibit enhanced phase resetting to advancing and delaying stimuli Selective pharmacological inhibition of CK1ε with PF4800567 enhances resetting Accelerated resetting is observed in central and peripheral clocks Accelerated resetting reduces physiological desynchrony Pilorz et al. reveal a new role for CK1ε in stabilizing the phase of the circadian clock. Using genetic and pharmacological targeting, they demonstrate that CK1ε dictates how rapidly the clock is reset by photic (light) and nonphotic (temperature) stimuli and thus highlight a novel target for reducing physiological disturbance in shift work.
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