Circadian rhythms are 24-h oscillations in behavior and physiology, which are
internally generated and function to anticipate the environmental changes associated with
the solar day. In mammals, the circadian system is organized in a hierarchical manner, in
which a master pacemaker in the suprachiasmatic nucleus (SCN) regulates downstream
oscillators in peripheral tissues . The clock mechanism in the SCN
consists of a network of transcriptional-translational feedback loops that drive rhythmic
24-h expression patterns of core clock components. The positive feedback loop includes
the key circadian rhythm regulators Clock homolog (CLOCK)
and Aryl hydrocarbon receptor nuclear translocator-like
(BMAL1) , .
BMAL1 forms heterodimers with
CLOCK and Neuronal PAS domain protein 2
(NPAS2) and drives transcription of Period homologs 1, 2, 3
PER3) and Cryptochromes 1 and 2
(CRY1, CRY2) , , . Negative feedback is achieved by PER:CRY heterodimers
that translocate from the cytoplasm to the nucleus to repress their own transcription by
acting on the CLOCK:BMAL1
complex , , .
The 24-h molecular clock is governed by post-translational modifications of the key
"clock" genes. Casein kinase I delta and
Casein kinase I epsilon phosphorylate
PER3 in the cytoplasm and promote
PER1, PER2 and
PER3 proteosomal degradation , , . CRY1 and
CRY2 are also phosphorylated by
Casein kinase I epsilon . In addition, Casein kinase I epsilon
phosphorylates BMAL1 and stimulates its transcriptional
Another regulatory loop is induced by
activating transcription of Nuclear receptor subfamily 1, group D, member 1
(REV-ERB alpha) and RAR-related orphan receptor A
(ROR-alpha). REV-ERB alpha and
ROR-alpha bind the same elements (ROREs) present in the
BMAL1 promoter. ROR-alpha
activates transcription of BMAL1, whereas
REV-ERB alpha represses the transcription process , , , .
Basic helix-loop-helix family, members e40 and e41
(DEC1 (Stra13), DEC2) are another set of circadian rhythm
regulators expressed in the suprachiasmic nucleus in a circadian fashion, with a peak in
the subjective day. BMAL1 induces DEC1
(Stra13) expression, and DEC1 (Stra13) and
DEC2 repress CLOCK:
BMAL1-induced transactivation of the
PER1 promoter , .
Expression of the main "clock" genes is mainly regulated by light and changes in
metabolic state. Photic entrainment promotes release of L-Glutamic
acid and Adenylate cyclase activating polypeptide 1
(PACAP) from the rethinohypothalamic tract.
L-Glutamic acid binds to the Glutamate receptor, ionotropic,
N-methyl D-aspartate 1 (NMDA receptor) and stimulates
Ca('2+) influx in neurons. Elevated
Ca('2+) levels promote Calcium/calmodulin-dependent protein
kinase II (CaMK II) activation via Calmodulin 2
II phosphorylates cAMP responsive element binding protein 1
(CREB1), which induces PER1 and
PER2 transcription , , , , . In addition, CAMK
II activates the V-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1)/ mitogen-activated protein kinase kinases 1, 2
mitogen-activated protein kinases 1-3 (ERK1/2) pathway
, . ERK1/2 activation leads
to CREB1 phosphorylation, most likely via Ribosomal protein
S6 kinase, 90kDa (p90Rsk) , , . In addition, L-Glutamic acid -induced
Ca('2+) increase promotes Nitric oxide synthase 1
(nNOS) activation via
Calmodulin binding or probably via CAMK
II phosphorylation of nNOS , . Released NO activates
Guanylate cyclase 1, soluble, which promotes
Cyclic GMP production. Cyclic
GMP activates Protein kinase, cGMP-dependent, type II
(Protein kinase G 2), which phosphorylates
CLOCK, thus promoting PER1
expression , , , .
Light-induced PACAP signaling also leads to
CREB1 phosphorylation and PER1
transcription , , . NO
also activates RAS, dexamethasone-induced 1
(Dexras1). Dexras1 in turn
activates ERK1/2 through an unknown mechanism , .
Changes in metabolic states also regulate the circadian machine. Changes in the ratio
of NAD('+) and NADH alter the
binding affinity of both CLOCK:BMAL1
to their DNA recognition sites. The reduced form NADH
strongly enhances DNA binding of the
whereas the oxidized form NAD('+) -inhibits binding . In addition, NPAS:BMAL1
heterodimers regulate transcription of Lactate dehydrogenase A
(LDHA), which catalyzes conversion of Pyruvic
acid into (S)-Lactic acid with consumption of
NADH and release of NAD('+).
Thus, cofactors could be part of a feedback mechanism controlling the molecular clock
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