Fig. 3.

Molecular mechanism of circadian clock. After Zeitgebers of light, temperature, eating/drinking, physical activity, and social cues are perceived and transmitted to SCN, the central circadian clock system synchronizes with geophysical time and feedbacks to the downstream brain regions and peripheral organs by nervous system and hormone release. Briefly, CLOCK and BMAL1 form positive transcription factor of a heterodimer complex to promote rhythmic transcriptions of PER, CRY, and clock-controlled genes (CCGs) by integrating with E-box enhancers. PER and CRY accumulate in cytoplasm through the day and then translocate back to nucleus to reduce CLOCK/BMAL1 activity by forming a heterodimer complex. PER/CRY complex is also subsequently disassembled and resolved after CLOCK/BMAL1 concentration is declined. The remained free PER in cytoplasm is phosphorylated by casein kinase Iε (CKIε), and subsequently being ubiquitinated and degraded. Moreover, nuclear receptors of orphan nuclear receptor (REV-ERBα) and retinoic acid related orphan receptor alpha (RORα) can also regulate CLOCK/BMAL1 complex, while REV-ERBα is phosphorylated by glycogen synthase kinase-3β (GSK3β) to transcriptionally repress BMAL1 but RORα induces it