FIGURE 1.

Molecular mechanism of the circadian clock and its physiological regulations: In the primary TTFL, as light strikes the retina, the impulses are routed by RHT in the SCN. The signals from the central clocks produced by SCN are transmitted to the peripheral organs as hormonal and neuronal signals, and as circadian outputs, several physiological functions are controlled. In the cytoplasm, CKIε and MAPK phosphorylate CLOCK and BMAL1. In the nucleus CLOCK/BMAL1 heterodimer binds to the Per, Cry, and other circadian genes through the E-box element present on the DNA and activates the transcription of these genes. PER and CRY proteins translocate to the cytoplasm and repress their transcription by interacting with CLOCK/BMAL1 heterodimer.DBP protein binds to the DBP binding site of the Per, Cry, and other circadian genes thus activating the transcription. The secondary TTFL is primarily regulated by transcriptional activation of the RORs and suppression of REV-ERBα. REV-ERBα binds to the ROR elements in the BMAL1 promoter, suppressing BMAL1 transcription, to guide the rhythmic oscillation of BMAL1. RORa and RORb which bind to the RORE, on the other hand, activate BMAL1 expression. E4bp4 activated by REV-ERBα represses the DBP. Abbreviations: BMAL1, Bone Muscle Arnt-like protein 1; CLOCK, Circadian Locomotor Output Cycles Kaput; CKIε, Casein Kinase ε; CRY, Cryptochrome; DBP, D-Box binding protein; E4bp4, E4 Binding Protein 4; MAPK, Mitogen-Activated Protein Kinase; PER, Period; REV-ERBα/NR1D1, Nuclear receptor subfamily 1, group D, member 1; RHT, Retinohypothalamic Tract; ROR, Retinoic acid receptor-related Orphan Receptor; RRE, ROR Responding Element; SCN, Suprachiasmatic Nucleus; TTFL, Transcription/Translational Feedback Loop.