scholarly journals Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Andrea Brenna ◽  
Iwona Olejniczak ◽  
Rohit Chavan ◽  
Jürgen A Ripperger ◽  
Sonja Langmesser ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Cyclin Dependent Kinase ◽  
Suprachiasmatic Nuclei ◽  
Nuclear Entry ◽  
Period 2 ◽  
Clock Component ◽  
Free Running ◽  
Free Running Period ◽  
Cryptochrome 1 ◽  
Cyclin Dependent Kinase 5

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here, we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Of note is that CDK5 may not exclusively phosphorylate PER2, but in addition may regulate other proteins that are involved in the clock mechanism. Taken together, it appears that CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by a derailed circadian clock.

scholarly journals Cyclin Dependent Kinase 5 (CDK5) Regulates the Circadian Clock

2019 ◽  
Author(s):  
Andrea Brenna ◽  
Iwona Olejniczak ◽  
Rohit Chavan ◽  
Jürgen A. Ripperger ◽  
Sonja Langmesser ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Cyclin Dependent Kinase ◽  
Suprachiasmatic Nuclei ◽  
Nuclear Entry ◽  
Period 2 ◽  
Clock Component ◽  
Free Running ◽  
Free Running Period ◽  
Cryptochrome 1 ◽  
Cyclin Dependent Kinase 5

AbstractCircadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by the circadian clock.

Regularly scheduled voluntary exercise synchronizes the mouse circadian clock

1991 ◽  
Vol 261 (4) ◽  
pp. R928-R933 ◽  
Author(s):  
D. M. Edgar ◽  
W. C. Dement
Keyword(s):  
Circadian Rhythms ◽  
Phase Shift ◽  
Circadian Clock ◽  
Wheel Running ◽  
External Environment ◽  
Voluntary Exercise ◽  
Wheel Rotation ◽  
Exercise Activity ◽  
Free Running ◽  
Free Running Period

Circadian rhythm entrainment has long been thought to depend exclusively on periodic cues in the external environment. However, evidence now suggests that appropriately timed vigorous activity may also phase shift the circadian clock. Previously it was not known whether levels of exercise/activity associated with spontaneous behavior provided sufficient feedback to phase shift or synchronize circadian rhythms. The present study investigated this issue by monitoring the sleep-wake, drinking, and wheel-running circadian rhythms of mice (Mus musculus) during unrestricted access to running wheels and when free wheel rotation was limited to either 12- or 6-h intervals with a fixed period of 24 h. Wheel rotation was controlled remotely. Mice spontaneously ran in wheels during scheduled access, and free-running sleep-wake and drinking circadian rhythms became entrained to scheduled exercise in 11 of 15 animals. However, steady-state entrainment was achieved only when exercise commenced several hours into the subjective night. The temporal placement of running during entrainment was related (r = 0.7003, P less than 0.02) to free-running period before entrainment. Mice with a free-running period less than 23.0 h did not entrain but exhibited relative coordination between free-running variables and the wheel availability schedule. Thus the circadian timekeeping system responds to temporal feedback arising from the timing of volitional exercise/activity, suggesting that the biological clock not only is responsive to periodic geophysical events in the external environment but also derives physiological feedback from the spontaneous activity behaviors of the organism.

scholarly journals Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock

2021 ◽  
Author(s):  
Yoshiaki Yamaguchi ◽  
Iori Murai ◽  
Kaoru Goto ◽  
Shotaro Doi ◽  
Huihua Zhou ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Dorsal Region ◽  
Circadian Expression ◽  
Delayed Initiation ◽  
Free Running ◽  
Responsive Element ◽  
Free Running Period ◽  
Orphan Gpcr

Background and Purpose: Gpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with no established physiological function in vivo. The purpose of this study was to determine the role of Gpr19 in the circadian clock system. Experimental Approach: We examined whether and how the master circadian clock neurons in the suprachiasmatic nucleus (SCN) express Gpr19. By analysing Gpr19-deficient (Gpr19−/−) mice, we asked whether Gpr19 has a role in modulating free-running period and light resetting capacity of the circadian clock. Key Results: Compared with the known common core clock genes, Gpr19 was identified to show several distinct yet limited features related to the circadian clock. Gpr19 mRNA was mainly expressed in the middle-to-dorsal region of the SCN. A conserved cAMP-responsive element within the Gpr19 promoter drove the circadian expression of Gpr19. Gpr19−/− mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity in a 12-h light/12-h dark cycle. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. Gpr19−/− mice had a reduced capacity for phase shift to early subjective night light. The defect was only observed for phase-delay, but not phase-advance, and accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral part of the SCN, in Gpr19−/− mice. Conclusion and Implications: Gpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and thus may be a potential target for alleviating circadian clock disorders.

scholarly journals Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshiaki Yamaguchi ◽  
Iori Murai ◽  
Kaoru Goto ◽  
Shotaro Doi ◽  
Huihua Zhou ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Light Exposure ◽  
Physiological Role ◽  
Delayed Initiation ◽  
Free Running ◽  
Responsive Element ◽  
Free Running Period ◽  
Ventral Area ◽  
Orphan Gpcr

AbstractGpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with currently no established physiological role in vivo. We characterized Gpr19 expression in the suprachiasmatic nucleus (SCN), the locus of the master circadian clock in the brain, and determined its role in the context of the circadian rhythm regulation. We found that Gpr19 is mainly expressed in the dorsal part of the SCN, with its expression fluctuating in a circadian fashion. A conserved cAMP-responsive element in the Gpr19 promoter was able to produce circadian transcription in the SCN. Gpr19−/− mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. In response to light exposure at night, Gpr19−/− mice had a reduced capacity for light-induced phase-delays, but not for phase-advances. This defect was accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral area of the SCN, in Gpr19−/− mice. Thus, our data demonstrate that Gpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and may provide a potential target option for modulating the circadian clock.

scholarly journals Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2

2018 ◽  
Vol 11 (556) ◽  
pp. eaau0715 ◽  
Author(s):  
JingJing Liu ◽  
Xianlin Zou ◽  
Tetsuya Gotoh ◽  
Anne M. Brown ◽  
Liang Jiang ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Ubiquitin Ligase ◽  
Posttranslational Modifications ◽  
Mammalian Cells ◽  
Tumor Development ◽  
Mouse Double Minute ◽  
Period 2 ◽  
Clock Component ◽  
Ubiquitin Ligase Complex ◽  
Double Minute

The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat–containing proteins (β-TrCPs), which are F-box–containing proteins that function as substrate recognition subunits of the SCFβ-TRCPubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis.

Emergence of altered circadian timing in a cholinergically supersensitive rat line

1999 ◽  
Vol 277 (4) ◽  
pp. R1171-R1178 ◽  
Author(s):  
Sally A. Ferguson ◽  
David J. Kennaway
Keyword(s):  
Onset Time ◽  
Neural Pathways ◽  
Suprachiasmatic Nuclei ◽  
Circadian Timing ◽  
Temperature Rhythm ◽  
Circadian Timing System ◽  
Free Running ◽  
Light Effects ◽  
Free Running Period

Mammalian circadian rhythms are controlled by the suprachiasmatic nuclei (SCN) in concert with light information. Several neurotransmitters and neural pathways modulate light effects on SCN timing. This study used a line of rat with an upregulated cholinergic system to investigate the role of acetylcholine in rhythmicity. With the use of a selective breeding program based on the thermic response to a cholinergic agonist, we developed a supersensitive (Sox) and subsensitive (Rox) rat line. The Sox rats showed an earlier onset time of melatonin rhythm under a 12:12-h light-dark photoperiod from generation 3 (3 ± 0.5 h after dark) compared with Rox rats (4.5 ± 0.1 h) and an earlier morning decline in temperature (0.9 ± 0.3 h before lights on) compared with Rox animals (0.1 ± 0.1 h). Furthermore, the Soxanimals displayed a significantly shorter free-running period of temperature rhythm than Rox rats (23.9 ± 0.04 and 24.3 ± 0.1 h, respectively, P < 0.05). The results suggest that the altered circadian timing of the Sox rats may be related to the cholinergic supersensitivity, intimating a role for acetylcholine in the circadian timing system.

scholarly journals Author response: Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock

2019 ◽  
Author(s):  
Andrea Brenna ◽  
Iwona Olejniczak ◽  
Rohit Chavan ◽  
Jürgen A Ripperger ◽  
Sonja Langmesser ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Author Response ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase 5

scholarly journals Optogenetic stimulation of VIPergic SCN neurons induces photoperiodic changes in the mammalian circadian clock

2021 ◽  
Author(s):  
Michael C. Tackenberg ◽  
Jacob J. Hughey ◽  
Douglas G. McMahon
Keyword(s):  
Ex Vivo ◽  
Day Length ◽  
Optogenetic Stimulation ◽  
Period 2 ◽  
Free Running ◽  
Free Running Period ◽  
The Brain ◽  
Long Photoperiod ◽  
Stimulation Of

SummaryCircadian clocks play key roles in how organisms respond to and even anticipate seasonal change in day length, or photoperiod. In mammals, photoperiod is encoded by the central circadian pacemaker in the brain, the suprachiasmatic nucleus (SCN). The subpopulation of SCN neurons that secrete the neuropeptide VIP mediate the transmission of light information within the SCN neural network, suggesting a role for these neurons in circadian plasticity in response to light information that has yet to be directly tested. Here, we used in vivo optogenetic stimulation of VIPergic SCN neurons followed by ex vivo PERIOD 2::LUCIFERASE (PER2::LUC) bioluminescent imaging to test whether activation of this SCN neuron sub-population can induce SCN network changes that are hallmarks of photoperiodic encoding. We found that optogenetic stimulation designed to mimic a long photoperiod indeed altered subsequent SCN entrained phase, increased the phase dispersal of PER2 rhythms within the SCN network, and shortened SCN free-running period – similar to the effects of a true extension of photoperiod. Optogenetic stimulation also induced analogous changes on related aspects of locomotor behavior in vivo. Thus, selective activation of VIPergic SCN neurons induces photoperiodic network plasticity in the SCN which underpins photoperiodic entrainment of behavior.

scholarly journals CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch

2018 ◽  
Vol 115 (23) ◽  
pp. 5986-5991 ◽  
Author(s):  
Rajesh Narasimamurthy ◽  
Sabrina R. Hunt ◽  
Yining Lu ◽  
Jean-Michel Fustin ◽  
Hitoshi Okamura ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Splice Variant ◽  
Carboxyl Terminus ◽  
Casein Kinase 1 ◽  
Multisite Phosphorylation ◽  
Period 2 ◽  
Cellular Environment ◽  
Clock Component ◽  
Biophysical Analysis ◽  
Carboxyl Terminal

Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation, and lengthen the period of the circadian clock. Here, we perform a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1δ/ε is indeed the priming kinase. We find that both CK1ε and a recently characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl-terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.

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