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Chapter 028. Sleep Disorders (Part 3)

Physiology of Circadian Rhythmicity The sleep-wake cycle is the most evident of the many 24-h rhythms in humans. Prominent daily variations also occur in endocrine, thermoregulatory, cardiac, pulmonary, renal, gastrointestinal, and neurobehavioral functions. At the molecular level, endogenous circadian rhythmicity is driven by self-sustaining transcriptional/translational feedback loops (Fig. 28-2). In evaluating a daily variation in humans, it is important to distinguish between those rhythmic components passively evoked by periodic environmental or behavioral changes (e.g., the increase in blood pressure and heart rate upon assumption of the upright posture) and those actively driven by an endogenous oscillatory process (e.g., the circadian. | Chapter 028. Sleep Disorders Part 3 Physiology of Circadian Rhythmicity The sleep-wake cycle is the most evident of the many 24-h rhythms in humans. Prominent daily variations also occur in endocrine thermoregulatory cardiac pulmonary renal gastrointestinal and neurobehavioral functions. At the molecular level endogenous circadian rhythmicity is driven by self-sustaining transcriptional translational feedback loops Fig. 28-2 . In evaluating a daily variation in humans it is important to distinguish between those rhythmic components passively evoked by periodic environmental or behavioral changes e.g. the increase in blood pressure and heart rate upon assumption of the upright posture and those actively driven by an endogenous oscillatory process e.g. the circadian variation in plasma cortisol that persists under a variety of environmental and behavioral conditions . Figure 28-2 Model of the molecular feedback loop at the core of the mammalian circadian clock. The positive element of the feedback loop is the transcriptional activation of the Perl gene and probably other clock genes by a heterodimer of the transcription factors CLOCK and BMAL1 also called MOP3 bound to an Ebox DNA regulatory element. The Perl transcript and its product the clock component PER1 protein accumulate in the cell cytoplasm. As it accumulates the PER1 protein is recruited into a multiprotein complex thought to contain other circadian clock component proteins such as cryptochromes CRYs Period proteins PERs and others. This complex is then transported into the cell nucleus across the dotted line where it functions as the negative element in the feedback loop - by inhibiting the activity of the CLOCK-BMAL1 transcription factor heterodimer. As a consequence of this action the concentration of PER1 and other clock proteins in the inhibitory complex falls allowing CLOCK-BMAL1 to activate transcription of Per1 and other genes and begin another cycle. The dynamics of the 24-h molecular cycle are .