Circadian cycles

Naturally Occurring Compounds. Many derivatives of iadole are found ia plants and animals where they are derived from the amino acid tryptophan. Several of these have important biological function or activity. Serotonin [50-67-9] (12) functions as a neurotransmitter and vasoconstrictor (35). Melatonin [73-31-4] (13) production is controlled daily by the circadian cycle and its physiological level iafluences, and seasonal rhythms ia humans and other species (36). Indole-3-acetic acid [87-51-4] (14) is a plant growth stimulant used ia several horticultural appHcations (37). 

It is most probable that sleep and waking stem from an inherent cycle of neuronal activity that can be influenced dramatically by changes in sensory stimulation. This is demonstrable not only in humans and laboratory animals, but also in invertebrates. Thus, while we cannot be sure that other animals sleep in the same way that we do, they do show a circadian cycle of motor activity. In some (nocturnal) species, such as the rat, this activity is actually highest during darkness. Even aplysia, the sea hare, has such a rhythm but this is more like that of humans in being maximally active during daylight (diurnal). 

At its most fundamental level, the circadian cycle rests on the influence of so-called clock genes . These genes have been studied most extensively in insects but they have also been found in humans. Their protein products enter the cell nucleus and regulate their own transcription. This feedback process is linked to exposure to light and so it is not surprising that visual inputs are important for maintenance of circadian rhythms. However, it is not the reception of specific visual information, transmitted in the optic nerve to the lateral geniculate nucleus (LGN) and visual cortex (i.e. visual discrimination), that is responsible for the rhythm but the more simple, almost subconscious, reception of light. 

The precise role of melatonin in sleep and waking is uncertain but it seems to act as a go-between for the light and biological cycles and evidence suggests that it has a reciprocal relationship with the SCN (Fig. 22.3). Its actions are mediated by (MLi) receptors which are found predominantly in the SCN as well as thalamic nuclei and the anterior pituitary. These are G protein-coupled receptors, with seven transmembrane domains, that inhibit adenylyl cyclase. Their activation by melatonin, or an MLi agonist such as 2-iodomelatonin, restores the impaired circadian cycle in aged rats. 

In a recent study, c-fos expression was examined in TMN neurons in spontaneously awake animals (Ko et al., 2003). These authors reported a strong correlation between c-fos expression in the TMN and the amount of wakefulness independent of the circadian cycle. In rats maintained on a normal 12 12 lightrdark cycle, wakefulness was increased and c-fos expression was also increased in the TMN during the dark period relative to the light period. In rats maintained in constant darkness, increased wakefulness and increased c-Fos protein in the TMN were observed during the subjective night, irrespective of the lighting condition. 

Our laboratory started to work on circadian rhythms by serendipity, while studying the liver-specific transcription of the serum albumin gene. We isolated a cDN A copy for a transcription factor that we dubbed DBP (for albumin promoter D-element Binding Protein). DBP, a basic leucine zipper (bZip) transcription factor, is the founding member of the PAR (proline-acidic amino acid rich)-domain bZip transcription factors, a small subfamily of bZip proteins consisting of DBP, TEF and HLF. It turned out that DBP protein and mRNA accumulation undergo circadian cycles with amplitudes in excess of one hundred-fold (Wuarin Schibler 1990). 

Akhtar RA, Reddy AB, Maywood ES et al 2002 Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12 540-550... 

To begin an examination of the fraction of false positives, we chose 14 of our cycling mRNAs at random and examined their cycling by real-time PCR. We could clearly confirm the cycling and microarray patterns for 10 of the 14 mRNAs, and the cycling was likely positive for two more. Only in two of the 14 cases was circadian cycling unlikely, based on the real-time results. We conclude that most of our 134 mRNAs are real cyclers and that false positives constitute only a minority of the 134 mRNAs. The number 134 is probably a gross underestimate. 

In the Drosophila circadian clock, three proteins are rhythmically phosphorylated throughout the circadian cycle PER, TIM and dCLK. The electrophoretic mobility of these three proteins all undergo changes during the circadian day by Western analysis. In all cases, phosphatase treatment reduced or eliminated the slower migrating bands, suggesting that the mobility shifts are due to phosphorylation (Edery et al 1994, Zeng et al 1996, Lee et al 1998). While there is evidence that DBT phosphorylates PER and SGG phosphorylates TIM, it is possible that other kinases phosphorylate these proteins as well. TIM, for instance, is phosphorylated by a tyrosine kinase before it is ubiquitinated and... 

The pineal gland appears also to play a role in maintaining the mammalian circadian cycle.1081-1083 The concentration of the pineal hormone melatonin (Fig. 27-11) as well as its precursor N-acetylserotonin and the enzyme serotonin N-acetyltransferase (Eq. 30-4) all fluctuate far more than do the concentrations of other metabolites during the 24-h cycle. These metabolites increase over 10-fold concentration at night and decrease by day. During the daytime the serotonin N-acyltransferase, which forms the precursor, is rapidly... 

The circadian cycle is not the only timing device used by animals. A short-term interval timer helps male doves to know how long to sit on a nest1085 and helps all of us in timing everyday tasks. 

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