Circadian clock mammalian

In all types of mammalian cells, the molecular mechanism underlying circadian clock function is based upon interconnected transcription/translation feedback loops [2] (Fig. 2). Two proteins that function as transcriptional... 

Ko CH, Takahashi JS (2006) Molecular components of the mammalian circadian clock. Hum Mol Genet 15 Spec No 2 R271-R277... 

Sancar, A., Regulation of the mammalian circadian clock by cryptochrome, J. Biol. Chem., 279, 34079, 2004. 

Partch, C. L. et al., Postranslational regulation of mammalian circadian clock by cryptochrome and proteinphosphatase 5, Proc Aarf Acad. Sci. USA, 103, 10467, 2006. Briggs, W.R., Christie, J.M., and Salomon, M., Phototropins a new family of flavinbinding blue light receptors in plants, Antioxid. Redox Signal, 3, 775, 2001. Briggs,W.R. et al.. The phototropin family of photoreceptors. Plant Cell, 13, 993, 2001. 

Glass, J. D., Grossman, G. H., Farnbauch L. 8r DiNardo, L. (2003). Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus. J. Neurosci. 23, 7451-60. 

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. 

Further extensions of the model are required to address the dynamical consequences of these additional regulatory loops and of the indirect nature of the negative feedback on gene expression. Such extended models have been proposed for Drosophila [112, 113] and mammals [113]. The model for the circadian clock mechanism in mammals is schematized in Fig. 3C. The presence of additional mRNA and protein species, as well as of multiple complexes formed between the various clock proteins, complicates the model, which is now governed by a system of 16 or 19 kinetic equations. Sustained or damped oscillations can occur in this model for parameter values corresponding to continuous darkness. As observed in the experiments on the mammalian clock. Email mRNA oscillates in opposite phase with respect to Per and Cry mRNAs [97]. The model displays the property of entrainment by the ED cycle... 

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]. 

For some parameter values the model for the mammalian clock fails to allow entrainment by 24-h LD cycles, regardless of the amplitude of the light-induced change in Per expression. The question arises whether there exists a syndrome corresponding to this mode of dynamic behavior predicted by the model. Indeed there exists such a syndrome, known as the non-24-h sleep-wake syndrome, in which the phase of the sleep-wake pattern continuously varies with respect to the LD cycle that is, the patient free-runs in LD conditions [117]. Disorders of the sleep-wake cycle associated with alterations in the dynamics of the circadian clock belong to the broad class of dynamical diseases [122, 123], although the term syndrome seems more appropriate for some of these conditions. 

J. C. Leloup and A. Goldbeter, Toward a detailed computational model for the mammalian circadian clock. Proc. Natl. Acad. Sci. USA 100, 7051-7056 (2003). 

Griffin EA Jr, Staknis D, Weitz CJ 1999 Light-independent role of CRYl and CRY2 in the mammalian circadian clock. Science 286 768—771 Hattar S, Liao HW, Takao M, Berson DM, Yau KW 2002 Melanopsin-containing retinal ganglion cells architecture, projections, and Intrinsic photosensitivity. Science 295 1065-1070... 

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... 

Shearman LP, Sriram S, Weaver DR et al 2000 Interacting molecular loops in the mammalian circadian clock. Science 288 1013-1019... 

Shigeyoshi Y, Taguchi K, Yamamoto S et al 1997 Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPerl transcript. Cell 91 1043—1053... 

Griffin EA Jr, Staknis D, Weitz CJ 1999 Light-independent role of CRYl and CRY2 in the mammalian circadian clock. Science 286 768—771... 

Zheng B, Albrecht U, Kaasik K et al 2001 Nonredundant roles of the mPerl and mPer2 genes in the mammalian circadian clock. Cell 105 683-694... 

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