Category: signaling
The mammalian circadian clock is a transcription-translation feedback loop (TTFL) with ~24h period — master oscillator in the suprachiasmatic nucleus (SCN, retinohypothalamic-entrained) + peripheral clocks in essentially every cell. Core positive limb: BMAL1 (ARNTL) heterodimerizes with CLOCK (or NPAS2 in some tissues) → bHLH-PAS transcription factors bind E-box elements → drive transcription of Per1/2/3, Cry1/2, and ~10–15% of all expressed genes. Core negative limb: PER + CRY accumulate over hours → dimerize + nuclear-translocate → repress BMAL1-CLOCK → drives the ~24h oscillation. Stabilizing loop: BMAL1-CLOCK also drives Rev-erbα/β (NR1D1/2 — repress BMAL1) and Rorα (activates BMAL1). Post-translational regulation: CK1δ/ε phosphorylates PER → degradation timing → period control (familial advanced sleep phase syndrome); β-TrCP-mediated PER/CRY ubiquitination; AMPK phosphorylates CRY1 → degradation. Therapeutic relevance: melatonin (MT1/MT2) advances/delays clock — chronotype + jet lag; ramelteon, tasimelteon, agomelatine are melatonergic; orexin receptor antagonists (suvorexant, lemborexant, daridorexant) target wake-promoting axis; lithium lengthens period via GSK-3β. Chronopharmacology: aspirin, statins, antihypertensives show time-of-day efficacy differences. Light is the dominant zeitgeber (SCN ipRGC → melatonin suppression); food is the dominant peripheral-clock zeitgeber. Cross-links: [[serotonin_melatonin_axis]] (melatonin biosynthesis), [[orexin_arousal_axis]] (counter-regulatory wake drive), [[hpa_axis]] (cortisol rhythm).