ABSTRACT
The circadian clock system regulates daily rhythms of physiology and behavior, such as the sleep-wake cycle and hormonal secretion, body temperature and mood [1]. These rhythms are entrained by environmental cues, light-dark (LD) cycles and food intake. In mammals, the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus incorporates environmental information and coordinates the phase of oscillators in peripheral cells, tissues and organs [2,3]. Light is one of the most potent environmental cues that enable the organisms to adapt to the 24-hour environmental LD cycle. Photic signals are delivered from the eye to the SCN via the retinohypothalamic tract, thereby mediating the entrainment of the circadian clock system [4]. The circadian clock system involves transcription-translation negative feedback loops of multiple clock genes and posttranscriptional modification and degradation of clock proteins [4-6] (Figure 1). The basic helix-loop-helix and Per-Arnt-Sim transcription fac-
tors CLOCK and BMAL1 form heterodimers and activate transcription of Period 1 (Per1), Per2, Per3, Cryptochrome 1 (Cry1), Cry2 and retinoidrelated orphan receptor α (Rorα), Rorβ, Rorγ, Rev-Erbα and Rev-Erbβ by binding to E-box motifs on their promoter regions. PER and CRY proteins gradually accumulate in the cytoplasm and phosphorylation of PER and CRY occurs with casein kinase Iδ (CKIδ) and CKIε. PER, CRY and CKI proteins form complexes that translocate to the nucleus and interact with CLOCK-BMAL1 heterodimers, thereby inhibiting transcription of the Per, Cry, Ror and Rev-Erb genes. Meanwhile, Bmal1 transcription is regulated positively by retinoid-related orphan receptor (ROR) and negatively by REV-ERB via the ROR element (RORE) motif on the Bmal1 promoter.
10.2 CIRCADIAN RHYTHM SLEEP DISORDERS
