Circadian Rhythm Signaling


Pathway Description

A circadian rhythm is an approximately 24 hour periodicity in the various biochemical and physiological processes of living beings. The pacemaker for generating circadian rhythm in mammals is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian oscillations are synchronized with environmental light cycles via several photoreception systems. The neurons of the SCN receive light input signals from the retina by way of the retinohypothalamic tract. The synchronization of circadian rhythm with the environmental light cycles involves transcription of several clock genes in the SCN. These clock proteins are part of a negative feedback loop, wherein positive elements induce the expression of negative regulators that in turn inhibit the transactivation of positive regulators.

Light sets off the pacemaker through an excitatory signal transduction pathway mediated by glutamate (Glu) leading to N-methyl-D-aspartic acid (NMDA) receptor activation. Glu activation of NMDA receptors induces phosphorylation of Ca2+/cAMP response element binding protein (CREB). In addition vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), which stimulate melatonin biosynthesis in the mammalian pineal organ, cause phosphorylation of CREB. Activated CREB can then trigger the transcription of period (Per) genes. Per genes are known to be positively regulated by other clock proteins like the CLOCK and brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) which, associated as heterodimers, bind to E-box enhancer elements. In addition to Per other clock genes like cryptochrome (Cry) and Vasopressin (Avp) are also upregulated by CLOCK/BMAL1. The upregulated clock proteins now inhibit the transctivation by CLOCK/BMAL1.

The nuclear entry of clock gene products is required to establish the negative feed back loop- a key step in proper circadian rhythm. Heterodimerization of clock proteins PER and CRY is required for translocation to the nucleus. Nuclear entry of PER can be regulated by mammalian casein kinase I (CK1). Once in the nucleus, PER and CRY proteins appear to differentially inhibit the transactivation by CLOCK/BMAL1. Proteins like REV-ERBa and DEC also regulate the transcriptional activation by CLOCK/BMAL1. In addition, CRY, PER, and BMAL1-CLOCK play bidirectional roles in transcription resulting in interactivating feedback loops. The expression of BMAL1 and CLOCK can be upregulated by CRY and PER. Such loops are believed to be important in the stability and persistence of circadian rhythm.

This pathway highlights the important components of circadian rhythm signaling.