cGMP-dependent protein kinase I, the circadian clock, sleep and learning (original) (raw)
Sleep
The finding that deletion or mutation of core circadian clock genes in both mice and flies induce unexpected alterations in sleep amount, sleep architecture and the recovery response to sleep deprivation, has led to new insights into functions of the circadian system that extend beyond its role as a regulator of the timing of the sleep-wake cycle. A key transcription factor in the transcriptional/translational feedback loop of mammalian circadian genes is BMAL1/Mop3, a heterodimeric partner to CLOCK. It was previously shown that mice deficient in the BMAL1/Mop3 gene become immediately arrhythmic in constant darkness and have reduced locomotor activity levels under entrained and constant conditions. In this study, we tested the hypothesis that the mammalian BMAL1/Mop3 gene would have regulatory effects on sleep-wake patterns. In mice with targeted deletion of the BMAL1/Mop3 gene, EEG/EMG sleep-wake patterns were recorded under entrained and free-running conditions as well as followin...
Sleep, 2005
The finding that deletion or mutation of core circadian clock genes in both mice and flies induce unexpected alterations in sleep amount, sleep architecture and the recovery response to sleep deprivation, has led to new insights into functions of the circadian system that extend beyond its role as a regulator of the timing of the sleep-wake cycle. A key transcription factor in the transcriptional/translational feedback loop of mammalian circadian genes is BMAL1/Mop3, a heterodimeric partner to CLOCK. It was previously shown that mice deficient in the BMAL1/Mop3 gene become immediately arrhythmic in constant darkness and have reduced locomotor activity levels under entrained and constant conditions. In this study, we tested the hypothesis that the mammalian BMAL1/Mop3 gene would have regulatory effects on sleep-wake patterns. In mice with targeted deletion of the BMAL1/Mop3 gene, EEG/EMG sleep-wake patterns were recorded under entrained and free-running conditions as well as followin...
Involvement of cGMP in cellular melatonin responses*
Biology of the Cell, 1999
Melatonin can enhance and suppress constitutive protein secretion from murine melanoma M2R cells in vitro in a cholera-toxin (CTX) sensitive process. In a number of tissues melatonin has been shown to modulate cGMP levels. The involvement of cGMP in melatonin responses in the melanoma cells was investigated. The effects of melatonin on melanoma cells cGMP and cGMP-phosphodiesterase activity and the effects of cGMP analogs on the melatonin-mediated modulation of protein secretion were studied. Melatonin reduced cGMP levels in the melanoma cells. CTX treatment had a similar and non-additive effect. The effects of melatonin on protein secretion were abrogated by ,activation of cGMP-dependent protein kinases. In addition, melatonin inhibited cGMP phosphodiesterase activity in these cells. The data presented indicate that inhibition of cGMP via a CTX sensitive G protein may be a major signal transduction pathway used by melatonin in melanoma cells.
BMC Neuroscience
Background: We have previously reported that the expression of circadian clock-genes increases in the cerebral cortex after sleep deprivation (SD) and that the sleep rebound following SD is attenuated in mice deficient for one or more clock-genes. We hypothesized that besides generating circadian rhythms, clock-genes also play a role in the homeostatic regulation of sleep. Here we follow the time course of the forebrain changes in the expression of the clock-genes period (per)-1, per2, and of the clock-controlled gene albumin D-binding protein (dbp) during a 6 h SD and subsequent recovery sleep in three inbred strains of mice for which the homeostatic sleep rebound following SD differs. We reasoned that if clock genes are functionally implicated in sleep homeostasis then the SD-induced changes in gene expression should vary according to the genotypic differences in the sleep rebound. Results: In all three strains per expression was increased when animals were kept awake but the rate of increase during the SD as well as the relative increase in per after 6 h SD were highest in the strain for which the sleep rebound was smallest; i.e., DBA/2J (D2). Moreover, whereas in the other two strains per1 and per2 reverted to control levels with recovery sleep, per2 expression specifically, remained elevated in D2 mice. dbp expression increased during the light period both during baseline and during SD although levels were reduced during the latter condition compared to baseline. In contrast to per2, dbp expression reverted to control levels with recovery sleep in D2 only, whereas in the two other strains expression remained decreased. Conclusion: These findings support and extend our previous findings that clock genes in the forebrain are implicated in the homeostatic regulation of sleep and suggest that sustained, high levels of per2 expression may negatively impact recovery sleep.
A non-circadian role for clock-genes in sleep homeostasis:a strain comparison
BMC Neuroscience, 2007
We have previously reported that the expression of circadian clock-genes increases in the cerebral cortex after sleep deprivation (SD) and that the sleep rebound following SD is attenuated in mice deficient for one or more clock-genes. We hypothesized that besides generating circadian rhythms, clock-genes also play a role in the homeostatic regulation of sleep. Here we follow the time course of the forebrain changes in the expression of the clock-genes period (per)-1, per2, and of the clock-controlled gene albumin D-binding protein (dbp) during a 6 h SD and subsequent recovery sleep in three inbred strains of mice for which the homeostatic sleep rebound following SD differs. We reasoned that if clock genes are functionally implicated in sleep homeostasis then the SD-induced changes in gene expression should vary according to the genotypic differences in the sleep rebound.
Circadian control of the sleep–wake cycle
Physiology & Behavior, 2007
It is beyond doubt that the timing of sleep is under control of the circadian pacemaker. Humans are a diurnal species; they sleep mostly at night, and they do so at approximately 24-h intervals. If they do not adhere to this general pattern, for instance when working night shifts or when travelling across time zones, they experience the stubborn influence of their circadian clock.
Cyclin-dependent Kinase 5 (Cdk5) Regulates the Function of CLOCK Protein by Direct Phosphorylation
Journal of Biological Chemistry, 2013
Background: Cdk5 is a kinase involved in the various neuronal processes. Results: Cdk5 directly phosphorylates CLOCK and regulates its transcriptional activity in association with altered stability and subcellular distribution. Conclusion: Cdk5 functions as a regulator of CLOCK protein. Significance: Our findings may provide mechanistic links between diverse Cdk5-mediated brain functions and the molecular clock. Circadian rhythm is a biological rhythm governing physiology and behavior with a period of ϳ24 h. At the molecular level, circadian output is controlled by a molecular clock composed of positive and negative feedback loops in transcriptional and post-translational processes. CLOCK is a transcription factor known as a central component of the molecular clock feedback loops generating circadian oscillation. Although CLOCK is known to undergo multiple post-translational modifications, the knowledge of their entities remains limited. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine-threonine kinase that is involved in various neuronal processes. Here, we report that Cdk5 is a novel regulator of CLOCK protein. Cdk5 phosphorylates CLOCK at the Thr-451 and Thr-461 residues in association with transcriptional activation of CLOCK. The Cdk5-dependent regulation of CLOCK function is mediated by alterations of its stability and subcellular distribution. These results suggest that Cdk5 is a novel regulatory component of the core molecular clock machinery. Circadian rhythm is an internally generated biological rhythm with a period of ϳ24 h under control of day/night cycle. Circadian rhythm enables our body to adapt to the environmental changes by optimizing a wide variety of physiological processes such as the sleep/wake cycle, hormonal response, and feeding behaviors (1-3). This biological rhythm is found in * This work was supported by grants (NRF-2012R1A2A2A01012923 and NRF-2012R1A4A1028200) from the Korean government (MSIP) and also supported under the framework of international cooperation program managed by the NRF of Korea (2012K2A1A2033117) and the Korea Brain Research Institute (KBRI) Basic Research Program of MSIP (2031-415).
PloS one, 2012
The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase...
New Developments in Sleep Research: Molecular Genetics, Gene Expression, and Systems Neurobiology
The Journal of Neuroscience, 2008
Understanding the mechanisms that underlie the control of sleep and wakefulness is a major research area in neuroscience. This mini-symposium review highlights some recent developments at the gene, molecular, cellular, and systems levels that have advanced this field. The studies discussed below use organisms ranging from flies to humans and focus on the interaction between the sleep homeostatic and circadian systems, the consequences of mutations in genes involved in the circadian clock on sleep timing, the effects of sleep deprivation on brain gene expression, the discovery of “sleep active” neurons in the cerebral cortex, the role of the hypocretin/orexin system in the maintenance of sleep and wakefulness, and the interaction between sleep and learning.