Circadian rhythms mammalian clock

Clock oscillation occurs first at a cellular level. The clock genes so far identified in mammals are structurally similar to those in Drosophila (Young Kay 2001). This suggests that mammals and Drosophila utilize similar components to generate circadian ( 24 h) rhythms. Mammalian clock research is now showing whether the core feedback loop of clock genes speculated to be present in Drosophila (Hardin et al 1990) is also conserved in mammals. 

Circadian Rhythms. Figure 1 Mammalian circadian system is organized as a hierarchy of multiple clocks thatfunction to synchronize timing of internal processes between each other and with the environment. See details in the text. 

A role for the 5-HT7 receptor in the regulation of circadian rhythms has been implicated. As discussed above, 5-HT has been known for some time to induce phase shifts in behavioral circadian rhythms and modulate neuronal activity in the suprachiasmatic nucleus, the likely site of the mammalian circadian clock. The pharmacological characteristics of the effect of 5-HT on circadian rhythms are consistent with 5-HT7 receptor. Moreover, mRNA for the 5-HT7 receptor is found in the suprachiasmatic nucleus. There is also increasing evidence that the 5-HT7 receptor may play a role in psychiatric disorders. The regional distribution of 5-HT7 receptors in brain includes limbic areas and cortex. Atypical antipsychotics, such as clozapine and risperidone, and some antidepressants display high affinity for this receptor. In the periphery, 5-HT7 receptors havebeenshown to mediate relaxation of vascular smooth muscle. 

The results obtained with the model for the mammalian circadian clock provide cues for circadian-rhythm-related sleep disorders in humans [117]. Thus permanent phase shifts in LD conditions could account for (a) the familial advanced sleep phase syndrome (FASPS) associated with PER hypopho-sphorylation [118, 119] and (b) the delayed sleep phase syndrome, which is also related to PER [120]. People affected by FASPS fall asleep around 7 30 p.m. and awake around 4 30 a.m. The duration of sleep is thus normal, but the phase is advanced by several hours. Moreover, the autonomous period measured for circadian rhythms in constant conditions is shorter [121]. The model shows that a decrease in the activity of the kinase responsible for PER phosphorylation is indeed accompanied by a reduction of the circadian period in continuous darkness and by a phase advance upon entrainment of the rhythm by the LD cycle [114]. 

Terazono H, Mutoh T, Yamaguchi S et al 2003 Adrenergic regulation of clock gene expression in mouse liver. Proc Natl Acad Sci USA 100 6795-6800 Tosini G, Menaker M 1996 Circadian rhythms in cultured mammalian retina. Science 272 419-421... 

Yamazaki S, AlonesV, Menaker M 2002a Interaction of the retina with suprachiasmatic pacemakers in the control of circadian behavior. J Biol Rhythms 17 315-329 Yamazaki S, Straume M, Tei H, Sakaki Y, Menaker M, Block GD 2002b Effects of aging on central and peripheral mammalian clocks. Proc Natl Acad Sci USA 99 10801-10806... 

Frisch et all 994, Yang Sehgal2001). These strains also have reasonable periods (22—26 h) with poor rhythm amplitudes, as evidenced by the poor penetrance of rhythmicity. Taken together, these data suggest that changes in clock gene transcription have limited effects on circadian period. Separate control of circadian rhythm amplitude on the one hand and period (or phase) on the other is also consistent with anatomical experiments in both the fly and mammalian system (Liu et al 1991, Low-Zeddies Takahashi 2001). 

Allada R, White NE, So WV, Hall JC, Rosbash M 1998 A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93 791-804... 

Reseaichers at Northwestern University used a kind of reverse-knockout approach to identify the Clock gene. The first gene providing the circadian rhythm of mammalian life has now been identified. 

Circadian clock-controlled rhythms provide most organisms with an orchestrated temporal programme that allows for appropriate timing of physiology (i.e. blood pressure, hormonal levels) and behaviour (i.e. alertness, sleep-wake cycle). The mammalian central circadian pacemaker resides in the suprachiasmatic nucleus (SCN) of the brain (Weaver 1998). At the molecular level, the core oscillator driving the mammahan clock consists of interconnected autoregulatory... 

In mammalian tissue culture cells, robust circadian gene expression can be entrained by 12 h temperature cycles with an amplitude of 4 °C (e.g. 37 °C versus 33 °C) (Brown et al 2002). We thus wondered whether physiological temperature rhythms, themselves circadian and with an amplitude of —4 °C in most mammals, could also sustain cyclic clock-gene transcription. To this end, we engineered a... 

Herzog, E. D., S. J. Aton, R. Numano, Y. Sakaki, and H. Tei, Temporal Precision in the Mammalian Circadian System A Reliable Clock from Less Reliable Neurons, J. Biol. Rhythms, 19, 35 (2004). 

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