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).
Organ Systems
nervous
endocrine
cardiovascular
digestive
immune-hematologic
Pathway Steps
light → SCN ipRGCs (melanopsin) → SCN clock entrainment — via glutamate + PACAP from retinohypothalamic tract → CREB → Per1/2 induction. The master clock sits in the hypothalamic SCN, entrained to the light-dark cycle by intrinsically photosensitive retinal ganglion cells (ipRGCs) using the pigment melanopsin. This light input aligns the otherwise ~24-h self-sustaining oscillator to external time, and the SCN then synchronizes peripheral clocks throughout the body.
BMAL1 + CLOCK / NPAS2 → E-box binding → Per1/2/3, Cry1/2, Rev-erbα/β, Rorα transcription — via positive limb; bHLH-PAS heterodimer. The positive limb: BMAL1 heterodimerizes with CLOCK (or NPAS2) and binds E-box elements to transcribe the clock’s own repressors (Per1/2/3, Cry1/2) plus the nuclear receptors Rev-erbα/β and Rorα. This single activator complex drives both arms of the feedback loops that generate the rhythm.
PER + CRY accumulating cytoplasm → PER-CRY nuclear translocation → BMAL1-CLOCK repression — via negative limb; ~24h delay defines period. The negative limb: PER and CRY accumulate in the cytoplasm, dimerize, and re-enter the nucleus to inhibit BMAL1-CLOCK — shutting off their own transcription. The built-in delay between transcription and this repression (set by protein accumulation and phosphorylation) is what gives the loop its ~24-h period.
Rev-erbα/β + Rorα → Bmal1 transcription rhythmic — via stabilizing accessory loop; nuclear receptors with heme cofactor (Rev-erb). A second, interlocked loop tunes the clock: Rev-erbα/β repress and Rorα activates Bmal1 transcription, generating the antiphase rhythm of BMAL1 itself. The Rev-erbs are heme-sensing, druggable nuclear receptors — linking the clock to metabolism and making this loop a target for chronotherapy.
CK1δ/ε → PER phosphorylation → β-TrCP ubiquitination → degradation — via period-length control; CK1δ mutation = familial advanced sleep phase. Timing is set post-translationally: casein kinase CK1δ/ε phosphorylates PER, creating a phosphodegron for β-TrCP-mediated ubiquitination and proteasomal degradation. The speed of PER turnover sets the period — the CK1 mutation behind familial advanced sleep-phase syndrome shortens it.
AMPK → CRY1 phosphorylation → degradation — via metabolic input — feeding-state couples peripheral clocks to nutrient status. Metabolism feeds back onto the clock: AMPK (the cellular energy sensor) phosphorylates CRY1 to promote its degradation, thereby advancing the clock. This is one molecular link by which nutrient state and feeding time entrain peripheral clocks, sometimes uncoupling them from the SCN’s light-driven rhythm.
SCN clock → pineal melatonin synthesis (night) — via multi-synaptic SCN → PVN → IML → SCG → pineal AANAT. As an output, the SCN drives nighttime melatonin synthesis by the pineal gland (via a multisynaptic sympathetic relay that light suppresses). Melatonin is the body’s hormonal “darkness” signal and a feedback cue to the SCN — the basis for its use in jet lag and circadian sleep disorders.
Known Modulators
melatonin (activator) — MT1 / MT2 (clock-resetting). low dose (0.3–0.5 mg) for phase-shifting; higher doses for sleep onset only