O'Neill John S, Maywood Elizabeth S, Hastings Michael H
Department of Clinical Neurosciences, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, UK.
Handb Exp Pharmacol. 2013(217):67-103. doi: 10.1007/978-3-642-25950-0_4.
Circadian clocks drive the daily rhythms in our physiology and behaviour that adapt us to the 24-h solar and social worlds. Because they impinge upon every facet of metabolism, their acute or chronic disruption compromises performance (both physical and mental) and systemic health, respectively. Equally, the presence of such rhythms has significant implications for pharmacological dynamics and efficacy, because the fate of a drug and the state of its therapeutic target will vary as a function of time of day. Improved understanding of the cellular and molecular biology of circadian clocks therefore offers novel approaches for therapeutic development, for both clock-related and other conditions. At the cellular level, circadian clocks are pivoted around a transcriptional/post-translational delayed feedback loop (TTFL) in which the activation of Period and Cryptochrome genes is negatively regulated by their cognate protein products. Synchrony between these, literally countless, cellular clocks across the organism is maintained by the principal circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. Notwithstanding the success of the TTFL model, a diverse range of experimental studies has shown that it is insufficient to account for all properties of cellular pacemaking. Most strikingly, circadian cycles of metabolic status can continue in human red blood cells, devoid of nuclei and thus incompetent to sustain a TTFL. Recent interest has therefore focused on the role of oscillatory cytosolic mechanisms as partners to the TTFL. In particular, cAMP- and Ca²⁺-dependent signalling are important components of the clock, whilst timekeeping activity is also sensitive to a series of highly conserved kinases and phosphatases. This has led to the view that the 'proto-clock' may have been a cytosolic, metabolic oscillation onto which evolution has bolted TTFLs to provide robustness and amplify circadian outputs in the form of rhythmic gene expression. This evolutionary ascent of the clock has culminated in the SCN, a true pacemaker to the innumerable clock cells distributed across the body. On the basis of findings from our own and other laboratories, we propose a model of the SCN pacemaker that synthesises the themes of TTFLs, intracellular signalling, metabolic flux and interneuronal coupling that can account for its unique circadian properties and pre-eminence.
昼夜节律时钟驱动着我们生理和行为的每日节律，使我们适应24小时的太阳和社会环境。由于它们影响新陈代谢的方方面面，其急性或慢性紊乱分别会损害身体和精神表现以及全身健康。同样，这种节律的存在对药物动力学和疗效也有重大影响，因为药物的命运及其治疗靶点的状态会随一天中的时间而变化。因此，更好地理解昼夜节律时钟的细胞和分子生物学为治疗开发提供了新方法，无论是与时钟相关的疾病还是其他疾病。在细胞水平上，昼夜节律时钟围绕转录/翻译后延迟反馈环（TTFL）运转，其中周期基因（Period）和隐花色素基因（Cryptochrome）的激活受到其同源蛋白质产物的负调控。整个生物体中这些几乎无数的细胞时钟之间的同步性由主要的昼夜节律起搏器——下丘脑视交叉上核（SCN）维持。尽管TTFL模型取得了成功，但一系列不同的实验研究表明，它不足以解释细胞起搏的所有特性。最引人注目的是，人类红细胞中代谢状态的昼夜节律周期可以持续，而红细胞没有细胞核，因此无法维持TTFL。因此，最近的研究兴趣集中在振荡性胞质机制作为TTFL伙伴的作用上。特别是，cAMP和Ca²⁺依赖性信号传导是时钟的重要组成部分，而计时活动也对一系列高度保守的激酶和磷酸酶敏感。这导致了一种观点，即“原时钟”可能是一种胞质代谢振荡，进化在其上附加了TTFL，以提供稳健性并以节律性基因表达的形式放大昼夜节律输出。时钟的这种进化发展最终形成了SCN，它是分布在全身无数时钟细胞的真正起搏器。基于我们自己和其他实验室的研究结果，我们提出了一个SCN起搏器模型，该模型综合了TTFL、细胞内信号传导、代谢通量和神经元间耦合等主题，能够解释其独特的昼夜节律特性和卓越性。
