scholarly journals Na+/Ca2+ exchanger mediates cold Ca2+ signaling conserved for temperature-compensated circadian rhythms

2021 ◽  
Vol 7 (18) ◽  
pp. eabe8132
Author(s):  
Naohiro Kon ◽  
Hsin-tzu Wang ◽  
Yoshiaki S. Kato ◽  
Kyouhei Uemoto ◽  
Naohiro Kawamoto ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Mammalian Cells ◽  
Temperature Compensation ◽  
Clock Genes ◽  
Common Mechanism ◽  
Behavioral Rhythms ◽  
Intracellular Ca ◽  
Dependent Protein ◽  
Biochemical Oscillations ◽  
Response To Temperature

Circadian rhythms are based on biochemical oscillations generated by clock genes/proteins, which independently evolved in animals, fungi, plants, and cyanobacteria. Temperature compensation of the oscillation speed is a common feature of the circadian clocks, but the evolutionary-conserved mechanism has been unclear. Here, we show that Na+/Ca2+ exchanger (NCX) mediates cold-responsive Ca2+ signaling important for the temperature-compensated oscillation in mammalian cells. In response to temperature decrease, NCX elevates intracellular Ca2+, which activates Ca2+/calmodulin-dependent protein kinase II and accelerates transcriptional oscillations of clock genes. The cold-responsive Ca2+ signaling is conserved among mice, Drosophila, and Arabidopsis. The mammalian cellular rhythms and Drosophila behavioral rhythms were severely attenuated by NCX inhibition, indicating essential roles of NCX in both temperature compensation and autonomous oscillation. NCX also contributes to the temperature-compensated transcriptional rhythms in cyanobacterial clock. Our results suggest that NCX-mediated Ca2+ signaling is a common mechanism underlying temperature-compensated circadian rhythms both in eukaryotes and prokaryotes.

scholarly journals Dissociation of Per1 and Bmal1 circadian rhythms in the suprachiasmatic nucleus in parallel with behavioral outputs

2017 ◽  
Vol 114 (18) ◽  
pp. E3699-E3708 ◽  
Author(s):  
Daisuke Ono ◽  
Sato Honma ◽  
Yoshihiro Nakajima ◽  
Shigeru Kuroda ◽  
Ryosuke Enoki ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Suprachiasmatic Nucleus ◽  
Clock Genes ◽  
Behavioral Rhythm ◽  
Calcium Indicator ◽  
Intracellular Ca ◽  
Regional Specificity ◽  
Free Running ◽  
Activity Onset ◽  
And Behavior

The temporal order of physiology and behavior in mammals is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of bioluminescence reporters, we monitored the circadian rhythms of the expression of clock genes Per1 and Bmal1 in the SCN of freely moving mice and found that the rate of phase shifts induced by a single light pulse was different in the two rhythms. The Per1-luc rhythm was phase-delayed instantaneously by the light presented at the subjective evening in parallel with the activity onset of behavioral rhythm, whereas the Bmal1-ELuc rhythm was phase-delayed gradually, similar to the activity offset. The dissociation was confirmed in cultured SCN slices of mice carrying both Per1-luc and Bmal1-ELuc reporters. The two rhythms in a single SCN slice showed significantly different periods in a long-term (3 wk) culture and were internally desynchronized. Regional specificity in the SCN was not detected for the period of Per1-luc and Bmal1-ELuc rhythms. Furthermore, neither is synchronized with circadian intracellular Ca2+ rhythms monitored by a calcium indicator, GCaMP6s, or with firing rhythms monitored on a multielectrode array dish, although the coupling between the circadian firing and Ca2+ rhythms persisted during culture. These findings indicate that the expressions of two key clock genes, Per1 and Bmal1, in the SCN are regulated in such a way that they may adopt different phases and free-running periods relative to each other and are respectively associated with the expression of activity onset and offset.

scholarly journals Period2 3′-UTR and microRNA-24 regulate circadian rhythms by repressing PERIOD2 protein accumulation

2017 ◽  
Vol 114 (42) ◽  
pp. E8855-E8864 ◽  
Author(s):  
Seung-Hee Yoo ◽  
Shihoko Kojima ◽  
Kazuhiro Shimomura ◽  
Nobuya Koike ◽  
Ethan D. Buhr ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Light Pulse ◽  
Protein Level ◽  
Temperature Compensation ◽  
Clock Genes ◽  
Protein Translation ◽  
Protein Accumulation ◽  
Free Running ◽  
Protein Oscillation

We previously created two PER2::LUCIFERASE (PER2::LUC) circadian reporter knockin mice that differ only in the Per2 3′-UTR region: Per2::Luc, which retains the endogenous Per2 3′-UTR and Per2::LucSV, where the endogenous Per2 3′-UTR was replaced by an SV40 late poly(A) signal. To delineate the in vivo functions of Per2 3′-UTR, we analyzed circadian rhythms of Per2::LucSV mice. Interestingly, Per2::LucSV mice displayed more than threefold stronger amplitude in bioluminescence rhythms than Per2::Luc mice, and also exhibited lengthened free-running periods (∼24.0 h), greater phase delays following light pulse, and enhanced temperature compensation relative to Per2::Luc. Analysis of the Per2 3′-UTR sequence revealed that miR-24, and to a lesser degree miR-30, suppressed PER2 protein translation, and the reversal of this inhibition in Per2::LucSV augmented PER2::LUC protein level and oscillatory amplitude. Interestingly, Bmal1 mRNA and protein oscillatory amplitude as well as CRY1 protein oscillation were increased in Per2::LucSV mice, suggesting rhythmic overexpression of PER2 enhances expression of Per2 and other core clock genes. Together, these studies provide important mechanistic insights into the regulatory roles of Per2 3′-UTR, miR-24, and PER2 in Per2 expression and core clock function.

scholarly journals Shared Components of the FRQ-Less Oscillator and TOR Pathway Maintain Rhythmicity in Neurospora

2021 ◽  
pp. 074873042199994
Author(s):  
Rosa Eskandari ◽  
Lalanthi Ratnayake ◽  
Patricia L. Lakin-Thomas
Keyword(s):  
Circadian Rhythms ◽  
Clock Genes ◽  
Nutrient Sensing ◽  
Mass Spectrometry Analysis ◽  
Growth Responses ◽  
Tor Pathway ◽  
Spectrometry Analysis ◽  
Binding Partner ◽  
Binding Partners ◽  
Free Running

Molecular models for the endogenous oscillators that drive circadian rhythms in eukaryotes center on rhythmic transcription/translation of a small number of “clock genes.” Although substantial evidence supports the concept that negative and positive transcription/translation feedback loops (TTFLs) are responsible for regulating the expression of these clock genes, certain rhythms in the filamentous fungus Neurospora crassa continue even when clock genes ( frq, wc-1, and wc-2) are not rhythmically expressed. Identification of the rhythmic processes operating outside of the TTFL has been a major unresolved area in circadian biology. Our lab previously identified a mutation ( vta) that abolishes FRQ-less rhythmicity of the conidiation rhythm and also affects rhythmicity when FRQ is functional. Further studies identified the vta gene product as a component of the TOR (Target of Rapamycin) nutrient-sensing pathway that is conserved in eukaryotes. We now report the discovery of TOR pathway components including GTR2 (homologous to the yeast protein Gtr2, and RAG C/D in mammals) as binding partners of VTA through co-immunoprecipitation (IP) and mass spectrometry analysis using a VTA-FLAG strain. Reciprocal IP with GTR2-FLAG found VTA as a binding partner. A Δ gtr2 strain was deficient in growth responses to amino acids. Free-running conidiation rhythms in a FRQ-less strain were abolished in Δ gtr2. Entrainment of a FRQ-less strain to cycles of heat pulses demonstrated that Δ gtr2 is defective in entrainment. In all of these assays, Δ gtr2 is similar to Δ vta. In addition, expression of GTR2 protein was found to be rhythmic across two circadian cycles, and functional VTA was required for GTR2 rhythmicity. FRQ protein exhibited the expected rhythm in the presence of GTR2 but the rhythmic level of FRQ dampened in the absence of GTR2. These results establish association of VTA with GTR2, and their role in maintaining functional circadian rhythms through the TOR pathway.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

scholarly journals Laminar shear stress upregulates endothelial Ca2+-activated K+ channels KCa2.3 and KCa3.1 via a Ca2+/calmodulin-dependent protein kinase kinase/Akt/p300 cascade

2013 ◽  
Vol 305 (4) ◽  
pp. H484-H493 ◽  
Author(s):  
Jun Takai ◽  
Alexandra Santu ◽  
Haifeng Zheng ◽  
Sang Don Koh ◽  
Masanori Ohta ◽  
...  
Keyword(s):  
Shear Stress ◽  
Transcriptional Activation ◽  
Static Condition ◽  
Fold Increase ◽  
Laminar Shear Stress ◽  
Human Coronary Artery ◽  
Intracellular Ca ◽  
Kinase Cascade ◽  
Dependent Protein ◽  
Laminar Shear

In endothelial cells (ECs), Ca2+-activated K+ channels KCa2.3 and KCa3.1 play a crucial role in the regulation of arterial tone via producing NO and endothelium-derived hyperpolarizing factors. Since a rise in intracellular Ca2+ levels and activation of p300 histone acetyltransferase are early EC responses to laminar shear stress (LS) for the transcriptional activation of genes, we examined the role of Ca2+/calmodulin-dependent kinase kinase (CaMKK), the most upstream element of a Ca2+/calmodulin-kinase cascade, and p300 in LS-dependent regulation of KCa2.3 and KCa3.1 in ECs. Exposure to LS (15 dyn/cm2) for 24 h markedly increased KCa2.3 and KCa3.1 mRNA expression in cultured human coronary artery ECs (3.2 ± 0.4 and 45 ± 10 fold increase, respectively; P < 0.05 vs. static condition; n = 8–30), whereas oscillatory shear (OS; ± 5 dyn/cm2 × 1 Hz) moderately increased KCa3.1 but did not affect KCa2.3. Expression of KCa2.1 and KCa2.2 was suppressed under both LS and OS conditions, whereas KCa1.1 was slightly elevated in LS and unchanged in OS. Inhibition of CaMKK attenuated LS-induced increases in the expression and channel activity of KCa2.3 and KCa3.1, and in phosphorylation of Akt (Ser473) and p300 (Ser1834). Inhibition of Akt abolished the upregulation of these channels by diminishing p300 phosphorylation. Consistently, disruption of the interaction of p300 with transcription factors eliminated the induction of these channels. Thus a CaMKK/Akt/p300 cascade plays an important role in LS-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes.

Restricted food access and light-dark: impact of conflicting zeitgebers on circadian rhythms of the rabbit

1993 ◽  
Vol 264 (4) ◽  
pp. R708-R715 ◽  
Author(s):  
B. Jilge ◽  
H. Stahle
Keyword(s):  
Circadian Rhythms ◽  
Phase Difference ◽  
Food Access ◽  
Activity Rhythm ◽  
Light Period ◽  
The Other ◽  
Behavioral Rhythms ◽  
Activity Component ◽  
Common Control ◽  
Free Running

Free-running circadian rhythms of rabbits were exposed to a 11:55-11:55-h light-dark (LD) schedule. After complete entrainment (63 +/- 22 days), the predominantly nocturnally active rabbits were exposed to an additional zeitgeber, restricted food access (RF), which was imposed during the light period. In five animals RF had the same period (T) as the LD cycle (23:50 h), and in five other animals TRF was 24:10 h. At a period of 23:50 h for both zeitgebers, the rhythms of four animals were stably entrained to RF, while in one animal a component of the rhythm broke away from RF and entrained to the LD zeitgeber. In animals exposed to zeitgebers of different periods most of the activity rhythm also entrained to RF, but 20 +/- 7% of the activity entrained to the LD zeitgeber. The light-entrained activity component merged with the RF component when the zeitgebers crossed, and decomposition occurred when the phase difference exceeded 4-6 h. The results indicate that two circadian oscillator systems exist in the rabbit, one entrained by light-dark cycles and the other by feeding-fasting cycles. Both exert common control over a number of overt behavioral rhythms.

scholarly journals Physical Interaction between Epidermal Growth Factor Receptor and DNA-dependent Protein Kinase in Mammalian Cells

1998 ◽  
Vol 273 (3) ◽  
pp. 1568-1573 ◽  
Author(s):  
Debdutta Bandyopadhyay ◽  
Mahitosh Mandal ◽  
Liana Adam ◽  
John Mendelsohn ◽  
Rakesh Kumar
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Mammalian Cells ◽  
Growth Factor Receptor ◽  
Physical Interaction ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Epidermal Growth

scholarly journals SIRT7 is a deacetylase of N4-acetylcytidine on ribosomal RNA

2021 ◽  
Author(s):  
Chenzhong Xu ◽  
Jin Zhang ◽  
Jie Zhang ◽  
Baohua Liu
Keyword(s):  
Circadian Rhythms ◽  
Ribosomal Rna ◽  
Genome Stability ◽  
Rna Stability ◽  
Translation Efficiency ◽  
Dependent Protein ◽  
First Time ◽  
Protein Deacetylase

AbstractN-acetyltransferase 10 catalyzes RNA N4-acetylcytidine (ac4C) modifications and thus regulates RNA stability and translation efficiency. However, the deacetylase for ac4C is unknown. SIRT7 was initially identified as an NAD+-dependent protein deacetylase and plays essential roles in genome stability, circadian rhythms, metabolism, and aging. In this study, we identified SIRT7 as a deacetylase of the ac4C of ribosomal (r)RNA for the first time and found it to be NAD+-independent. Our data highlight the important role of SIRT7 in rRNA ac4C modification and suggest an additional epitranscriptional regulation of aging.

Ambient Temperature as a Strong Zeitgeber of Circadian Rhythms in Response to Temperature Sensitivity and Poor Heat Dissipation Abilities in Subterranean African Mole-Rats

2021 ◽  
pp. 074873042110342
Author(s):  
Daniel W. Hart ◽  
Barry van Jaarsveld ◽  
Kiara G. Lasch ◽  
Kerryn L. Grenfell ◽  
Maria K. Oosthuizen ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Ambient Temperature ◽  
Heat Dissipation ◽  
Direct Consequence ◽  
Ecological Constraints ◽  
Photic Entrainment ◽  
Mole Rat ◽  
Intimate Link ◽  
Response To Temperature ◽  
First Time

Mammals have evolved circadian rhythms in internal biological processes and behaviors, such as locomotor activity (LA), to synchronize to the environmental conditions they experience. Photic entrainment of LA has been well established; however, non-photic entrainment, such as ambient temperature ( Ta), has received much less attention. To address this dearth of knowledge, we exposed two subterranean endothermic-homeothermic African mole-rat species, the solitary Cape mole-rat ( Georychus capensis [GC]) and social Mahali mole-rat ( Cryptomys hottentotus mahali [CHM]), to varying Ta cycles in the absence of light. We showed that the LA rhythms of these two species entrain to Ta cycles and that the majority of LA occurred during the coolest 12-h period. LA confined to the coolest Ta periods may be the direct consequence of the poor heat dissipation abilities of African mole-rats brought about by physiological and ecological constraints. Recently, it has been hypothesized that Ta is only a strong zeitgeber for circadian rhythms in species whose thermoregulatory abilities are sensitive to changes in Ta (i.e., heterotherms and ectotherms), which previously has excluded endothermic-homeothermic mammals. However, this study demonstrates that Ta is a strong zeitgeber or entrainer for circadian rhythms of LA in subterranean endothermic-homeothermic mammals as a consequence of their sensitivity to changes in Ta brought about by their poor heat dissipation abilities. This study reinforces the intimate link between circadian rhythms and thermoregulation and conclusively, for the first time, provides evidence that Ta is a strong zeitgeber for endothermic-homeothermic mammals.

scholarly journals Modulatory Effects of Circadian Rhythms in the Lung Adenocarcinoma Tumor Microenvironment

2021 ◽  
Author(s):  
Qianzhun Huang ◽  
Xiaoyang Su ◽  
Ning Fang ◽  
Jian Huang
Keyword(s):  
Tumor Microenvironment ◽  
Circadian Rhythms ◽  
Lung Adenocarcinoma ◽  
Circadian Clock ◽  
Drug Sensitivity ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Functional Enrichment ◽  
Expression Levels ◽  
Circadian Clock Genes

Abstract Background: Dysregulated circadian dynamic balance is strongly associated with cancer development. However, biological functions of circadian rhythms in lung adenocarcinoma (LUAD) have not been elucidated. This study aimed at valuating the modulatory effects of circadian rhythms in the LUAD tumor microenvironment.Methods: Multiple open-source bioinformatics research platforms are used to comprehensively elucidate the expression level, prognosis, potential biological function, drug sensitivity, and immune microenvironment of circadian clock genes in LUAD.Results: Most circadian clock genes in LUAD are dysregulated and are strongly correlated with patient prognosis, and missense mutations at splicing sites of these genes. Besides, these genes are closely associated with some well-known cancer-related marker pathways, which are mainly involved in the inhibition of the Apoptosis, Cell cycle, and DNA Damage Response Pathway. Furthermore, functional enrichment analysis revealedthat circadian clock genes regulate transcription factor activities and circadian rhythms in LUAD tissues. As for drug sensitivity, high expression of CLOCK, CRY1, and NR1D2 as well as suppressedPER2 and CRY2 expression levels are associated with drug resistance. The expression levels of circadian clock genes in LUAD correlate with immune infiltration and are involved in the regulation of immunosuppression.Conclusions: Our multi-omics analysis provides a more comprehensive understanding of the molecular mechanisms of the circadian clock genes in LUAD and provides new insights for a more precise screening of prognostic biomarkers and immunotherapy.

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