Circadian clocks allow organisms to anticipate repetitive changes in their environment such as food availability, temperature, and predation. While they most clearly manifest at the behavioral level, driving sleep-wake cycles, for example, they also provide critical temporal regulation at the level of individual tissues. Circadian clocks within organs act to ensure that each tissue is functioning in a coordinated manner to anticipate the needs of the organism as a whole but also allow for adaptation of organs to their local environment. One critical aspect of this environment is energy availability, which is communicated at the cellular level via changes in metabolites such as ATP, calcium, and NADH. AMP-activated protein kinase (AMPK) is both sensitive to fluctuations in secondary metabolites and capable of resetting the circadian clock via destabilization of the core clock components CRY and PER. Phosphorylation of serine 71 of CRY1 by AMPK destabilizes CRY1 by decreasing its interaction with binding partner PER2, thus enabling greater association with the SCF complex substrate adaptor FBXL3. Here, we describe a transgenic mouse harboring germline mutation of CRY1 serine 71 to alanine. Unexpectedly, this mutation does not affect the steady-state level of CRY1 protein in mouse livers or quadriceps. We also did not detect changes in either behavioral or molecular circadian rhythms, but female Cry1S71A mice exhibit decreased voluntary locomotor activity compared with wild-type littermates. Together, these findings suggest that phosphorylation of CRY1 serine 71 is not required for the regulation of circadian rhythms under normal physiological conditions. However, it may be involved in responding to metabolic challenges or in other aspects of physiology that contribute to voluntary activity levels.

中文翻译：

---

CRY1丝氨酸71的磷酸化可改变自愿活动，但不能改变体内昼夜节律。

昼夜节律时钟可使生物体预测其环境的重复变化，例如食物供应，温度和捕食。例如，尽管它们在行为水平上最明显地体现出来，例如驱动睡眠-觉醒周期，但它们在各个组织的水平上也提供了关键的时间调节。器官内的生物钟确保每个组织以协调的方式运作，以预测整个生物体的需求，但也可以使器官适应其当地环境。这种环境的一个关键方面是能量的可用性，它通过代谢物（例如ATP，钙和NADH）的变化在细胞水平上传递。AMP激活的蛋白激酶（AMPK）既对次级代谢产物的波动敏感，又能够通过使核心时钟成分CRY和PER不稳定来重置生物钟。AMPK使CRY1的丝氨酸71磷酸化，通过减少CRY1与结合伴侣PER2的相互作用来使CRY1不稳定，从而使它与SCF复合物底物衔接子FBXL3具有更大的缔合。在这里，我们描述了一个包含CRY1丝氨酸71到丙氨酸的种系突变的转基因小鼠。出乎意料的是，这种突变不会影响小鼠肝脏或股四头肌中CRY1蛋白的稳态水平。我们也没有检测到行为或分子昼夜节律的变化，但雌性Cry1S71A小鼠与野生型同窝仔相比表现出降低的自发运动能力。一起，这些发现表明在正常生理条件下调节昼夜节律不需要CRY1丝氨酸71的磷酸化。但是，它可能参与对代谢挑战的响应或有助于自愿活动水平的生理学其他方面。