Advertisement

Cellular Mechanisms of Circadian Pacemaking: Beyond Transcriptional Loops

  • John S. O’NeillEmail author
  • Elizabeth S. Maywood
  • Michael H. Hastings
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 217)

Abstract

Circadian clocks drive the daily rhythms in our physiology and behaviour that adapt us to the 24-h solar and social worlds. Because they impinge upon every facet of metabolism, their acute or chronic disruption compromises performance (both physical and mental) and systemic health, respectively. Equally, the presence of such rhythms has significant implications for pharmacological dynamics and efficacy, because the fate of a drug and the state of its therapeutic target will vary as a function of time of day. Improved understanding of the cellular and molecular biology of circadian clocks therefore offers novel approaches for therapeutic development, for both clock-related and other conditions. At the cellular level, circadian clocks are pivoted around a transcriptional/post-translational delayed feedback loop (TTFL) in which the activation of Period and Cryptochrome genes is negatively regulated by their cognate protein products. Synchrony between these, literally countless, cellular clocks across the organism is maintained by the principal circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. Notwithstanding the success of the TTFL model, a diverse range of experimental studies has shown that it is insufficient to account for all properties of cellular pacemaking. Most strikingly, circadian cycles of metabolic status can continue in human red blood cells, devoid of nuclei and thus incompetent to sustain a TTFL. Recent interest has therefore focused on the role of oscillatory cytosolic mechanisms as partners to the TTFL. In particular, cAMP- and Ca2+-dependent signalling are important components of the clock, whilst timekeeping activity is also sensitive to a series of highly conserved kinases and phosphatases. This has led to the view that the ‘proto-clock’ may have been a cytosolic, metabolic oscillation onto which evolution has bolted TTFLs to provide robustness and amplify circadian outputs in the form of rhythmic gene expression. This evolutionary ascent of the clock has culminated in the SCN, a true pacemaker to the innumerable clock cells distributed across the body. On the basis of findings from our own and other laboratories, we propose a model of the SCN pacemaker that synthesises the themes of TTFLs, intracellular signalling, metabolic flux and interneuronal coupling that can account for its unique circadian properties and pre-eminence.

Keywords

Intracellular Circadian rhythms Signal transduction Metabolic regulation SCN Post-translational Cytoscillator 

Notes

Acknowledgements

The authors wish to thank Paul Margiotta for graphical support, as well as G. Churchill, E. Herzog, D. Welsh and C. Allen for their helpful discussion and suggestions. JON is supported by The Wellcome Trust [093734/Z/10/Z]. ESM and MHH are funded by the Medical Research Council. No competing interests exist.

References

  1. Abraham U et al (2010) Coupling governs entrainment range of circadian clocks. Mol Syst Biol 6:438PubMedCrossRefGoogle Scholar
  2. Akhtar RA et al (2002) Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12(7):540–550PubMedCrossRefGoogle Scholar
  3. An S et al (2011) Vasoactive intestinal polypeptide requires parallel changes in adenylate cyclase and phospholipase C to entrain circadian rhythms to a predictable phase. J Neurophysiol 105(5):2289–2296PubMedCrossRefGoogle Scholar
  4. Antoch MP, Kondratov RV (2013) Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  5. Asher G et al (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134(2):317–328PubMedCrossRefGoogle Scholar
  6. Atkinson SE et al (2011) Cyclic AMP signaling control of action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus. J Biol Rhythms 26(3): 210–220PubMedCrossRefGoogle Scholar
  7. Aton SJ et al (2005) Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 8(4):476–483PubMedGoogle Scholar
  8. Aton SJ et al (2006) GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. Proc Natl Acad Sci USA 103(50):19188–19193PubMedCrossRefGoogle Scholar
  9. Baez-Ruiz A, Diaz-Munoz M (2011) Chronic inhibition of endoplasmic reticulum calcium-release channels and calcium-ATPase lengthens the period of hepatic clock gene Per1. J Circadian Rhythms 9:6PubMedCrossRefGoogle Scholar
  10. Berridge MJ (1997) The AM and FM of calcium signalling. Nature 386(6627):759–760PubMedCrossRefGoogle Scholar
  11. Blake WJ et al (2003) Noise in eukaryotic gene expression. Nature 422(6932):633–637PubMedCrossRefGoogle Scholar
  12. Brody S, Harris S (1973) Circadian rhythms in neurospora: spatial differences in pyridine nucleotide levels. Science 180(85):498–500PubMedCrossRefGoogle Scholar
  13. Brown TM, Piggins HD (2007) Electrophysiology of the suprachiasmatic circadian clock. Prog Neurobiol 82(5):229–255PubMedCrossRefGoogle Scholar
  14. Buhr ED, Takahashi JS (2013) Molecular components of the mammalian circadian clock. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  15. Buhr ED, Yoo SH, Takahashi JS (2010) Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330(6002):379–385PubMedCrossRefGoogle Scholar
  16. Bunger MK et al (2000) Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103(7):1009–1017PubMedCrossRefGoogle Scholar
  17. Cao R et al (2011) Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. Neuroscience 181:79–88PubMedCrossRefGoogle Scholar
  18. Castel M, Morris J, Belenky M (1996) Non-synaptic and dendritic exocytosis from dense-cored vesicles in the suprachiasmatic nucleus. Neuroreport 7(2):543–547PubMedCrossRefGoogle Scholar
  19. Cavallari N et al (2011) A blind circadian clock in cavefish reveals that opsins mediate peripheral clock photoreception. PLoS Biol 9(9):e1001142PubMedCrossRefGoogle Scholar
  20. Chen R et al (2009) Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism. Mol Cell 36(3):417–430PubMedCrossRefGoogle Scholar
  21. Chen Z et al (2012) Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc Natl Acad Sci USA 109(1):101–106PubMedCrossRefGoogle Scholar
  22. Cheng HY et al (2007) microRNA modulation of circadian-clock period and entrainment. Neuron 54(5):813–829PubMedCrossRefGoogle Scholar
  23. Cheng KT et al (2011) Local Ca(2)+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca(2)+ signals required for specific cell functions. PLoS Biol 9(3):e1001025PubMedCrossRefGoogle Scholar
  24. Cheong JK, Virshup DM (2011) Casein kinase 1: complexity in the family. Int J Biochem Cell Biol 43(4):465–469PubMedCrossRefGoogle Scholar
  25. Cohen JE, Fields RD (2006) CaMKII inactivation by extracellular Ca(2+) depletion in dorsal root ganglion neurons. Cell Calcium 39(5):445–454PubMedCrossRefGoogle Scholar
  26. Colwell CS (2011) Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci 12(10):553–569PubMedCrossRefGoogle Scholar
  27. Dallmann R et al (2012) The human circadian metabolome. Proc Natl Acad Sci USA 109(7): 2625–2629PubMedCrossRefGoogle Scholar
  28. Dardente H et al (2008) Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals. PLoS One 3(10):e3530PubMedCrossRefGoogle Scholar
  29. Debruyne JP et al (2006) A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50(3):465–477PubMedCrossRefGoogle Scholar
  30. Deery MJ et al (2009) Proteomic analysis reveals the role of synaptic vesicle cycling in sustaining the suprachiasmatic circadian clock. Curr Biol 19(23):2031–2036PubMedCrossRefGoogle Scholar
  31. Del Valle-Perez B et al (2011) Coordinated action of CK1 isoforms in canonical Wnt signaling. Mol Cell Biol 31(14):2877–2888PubMedCrossRefGoogle Scholar
  32. Dibner C et al (2009) Circadian gene expression is resilient to large fluctuations in overall transcription rates. EMBO J 28(2):123–134PubMedCrossRefGoogle Scholar
  33. Dickinson BC, Chang CJ (2011) Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat Chem Biol 7(8):504–511PubMedCrossRefGoogle Scholar
  34. Dioum EM et al (2002) NPAS2: a gas-responsive transcription factor. Science 298(5602): 2385–2387PubMedCrossRefGoogle Scholar
  35. Doherty CJ, Kay SA (2010) Circadian control of global gene expression patterns. Annu Rev Genet 44:419–444PubMedCrossRefGoogle Scholar
  36. Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125(3):497–508PubMedCrossRefGoogle Scholar
  37. Doi M et al (2011) Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus. Nat Commun 2:327PubMedCrossRefGoogle Scholar
  38. Durgan DJ et al (2012) O-GlcNAcylation, novel post-translational modification linking myocardial metabolism and cardiomyocyte circadian clock. J Biol Chem 286(52):44606–44619CrossRefGoogle Scholar
  39. Edgar RS et al (2012) Peroxiredoxins are conserved markers of circadian rhythms. Nature 485(7399):459–464PubMedGoogle Scholar
  40. Edmunds LN Jr (1983) Chronobiology at the cellular and molecular levels: models and mechanisms for circadian timekeeping. Am J Anat 168(4):389–431PubMedCrossRefGoogle Scholar
  41. Ehlen JC, Paul KN (2009) Regulation of light’s action in the mammalian circadian clock: role of the extrasynaptic GABAA receptor. Am J Physiol Regul Integr Comp Physiol 296(5):R1606–R1612PubMedCrossRefGoogle Scholar
  42. Eide EJ et al (2005) Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 25(7):2795–2807PubMedCrossRefGoogle Scholar
  43. Engelmann W, Bollig I, Hartmann R (1976) The effects of lithium ions on circadian rhythms. Arzneimittelforschung 26(6):1085–1086PubMedGoogle Scholar
  44. Etchegaray JP et al (2011) Casein kinase 1 delta (CK1delta) regulates period length of the mouse suprachiasmatic circadian clock in vitro. PLoS One 5(4):e10303CrossRefGoogle Scholar
  45. Fan Y et al (2007) Cycling of CRYPTOCHROME proteins is not necessary for circadian-clock function in mammalian fibroblasts. Curr Biol 17(13):1091–1100PubMedCrossRefGoogle Scholar
  46. Gamble KL et al (2007) Gastrin-releasing peptide mediates light-like resetting of the suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation. J Neurosci 27(44):12078–12087PubMedCrossRefGoogle Scholar
  47. Gentric G, Celton-Morizur S, Desdouets C (2012) Polyploidy and liver proliferation. Clin Res Hepatol Gastroenterol 36(1):29–34PubMedCrossRefGoogle Scholar
  48. Godinho SI et al (2007) The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316(5826):897–900PubMedCrossRefGoogle Scholar
  49. Golombek DA et al (2004) Signaling in the mammalian circadian clock: the NO/cGMP pathway. Neurochem Int 45(6):929–936PubMedCrossRefGoogle Scholar
  50. Gompf HS, Irwin RP, Allen CN (2006) Retrograde suppression of GABAergic currents in a subset of SCN neurons. Eur J Neurosci 23(12):3209–3216PubMedCrossRefGoogle Scholar
  51. Granshaw T, Tsukamoto M, Brody S (2003) Circadian rhythms in Neurospora crassa: farnesol or geraniol allow expression of rhythmicity in the otherwise arrhythmic strains frq10, wc-1, and wc-2. J Biol Rhythms 18(4):287–296PubMedCrossRefGoogle Scholar
  52. Gupta N, Ragsdale SW (2011) Thiol-disulfide redox dependence of heme binding and heme ligand switching in nuclear hormone receptor rev-erb{beta}. J Biol Chem 286(6):4392–4403PubMedCrossRefGoogle Scholar
  53. Hardie DG (2011) AMP-activated protein kinase–an energy sensor that regulates all aspects of cell function. Genes Dev 25(18):1895–1908PubMedCrossRefGoogle Scholar
  54. Hastings MH, Maywood ES, O’Neill JS (2008) Cellular circadian pacemaking and the role of cytosolic rhythms. Curr Biol 18(17):R805–R815PubMedCrossRefGoogle Scholar
  55. Herzog ED et al (2004) Temporal precision in the mammalian circadian system: a reliable clock from less reliable neurons. J Biol Rhythms 19(1):35–46PubMedCrossRefGoogle Scholar
  56. Hirota T et al (2008) A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta. Proc Natl Acad Sci USA 105(52): 20746–20751PubMedCrossRefGoogle Scholar
  57. Hirota T et al (2011) High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIalpha as a clock regulatory kinase. PLoS Biol 8(12):e1000559CrossRefGoogle Scholar
  58. Hirota T et al (2012) Identification of small molecule activators of cryptochrome. Science 337(6098):1094–1097PubMedCrossRefGoogle Scholar
  59. Iitaka C et al (2005) A role for glycogen synthase kinase-3beta in the mammalian circadian clock. J Biol Chem 280(33):29397–29402PubMedCrossRefGoogle Scholar
  60. Ikeda M et al (2003) Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons. Neuron 38(2):253–263PubMedCrossRefGoogle Scholar
  61. Isojima Y et al (2009) CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc Natl Acad Sci USA 106(37):15744–15749PubMedCrossRefGoogle Scholar
  62. Jiang YJ et al (2000) Notch signalling and the synchronization of the somite segmentation clock. Nature 408(6811):475–479PubMedCrossRefGoogle Scholar
  63. Johnson CH (1999) Forty years of PRCs–what have we learned? Chronobiol Int 16(6):711–743PubMedCrossRefGoogle Scholar
  64. Kaasik K, Lee CC (2004) Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature 430(6998):467–471PubMedCrossRefGoogle Scholar
  65. Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82(3):769–824PubMedGoogle Scholar
  66. Khalsa SB et al (1996) Evidence for a central role of transcription in the timing mechanism of a circadian clock. Am J Physiol 271(5 Pt 1):C1646–C1651PubMedGoogle Scholar
  67. Kholodenko BN, Hancock JF, Kolch W (2010) Signalling ballet in space and time. Nat Rev Mol Cell Biol 11(6):414–426PubMedCrossRefGoogle Scholar
  68. Kim DY et al (2005) Voltage-gated calcium channels play crucial roles in the glutamate-induced phase shifts of the rat suprachiasmatic circadian clock. Eur J Neurosci 21(5):1215–1222PubMedCrossRefGoogle Scholar
  69. Kim TD et al (2007) Rhythmic control of AANAT translation by hnRNP Q in circadian melatonin production. Genes Dev 21(7):797–810PubMedCrossRefGoogle Scholar
  70. Kim DY et al (2010) hnRNP Q and PTB modulate the circadian oscillation of mouse Rev-erb alpha via IRES-mediated translation. Nucleic Acids Res 38(20):7068–7078PubMedCrossRefGoogle Scholar
  71. King DP, Takahashi JS (2000) Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci 23:713–742PubMedCrossRefGoogle Scholar
  72. King VM et al (2003) A hVIPR transgene as a novel tool for the analysis of circadian function in the mouse suprachiasmatic nucleus. Eur J Neurosci 17(11):822–832CrossRefGoogle Scholar
  73. Kloss B et al (1998) The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94(1):97–107PubMedCrossRefGoogle Scholar
  74. Ko CH et al (2010) Emergence of noise-induced oscillations in the central circadian pacemaker. PLoS Biol 8(10):e1000513PubMedCrossRefGoogle Scholar
  75. Kononenko NI, Medina I, Dudek FE (2004) Persistent subthreshold voltage-dependent cation single channels in suprachiasmatic nucleus neurons. Neuroscience 129(1):85–92PubMedCrossRefGoogle Scholar
  76. Koyanagi S et al (2011) cAMP response element-mediated transcription by activating transcription factor-4 (ATF4) is essential for circadian expression of the Period2 gene. J Biol Chem 286:32416–32423PubMedCrossRefGoogle Scholar
  77. Kurabayashi N et al (2010) DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 30(7):1757–1768PubMedCrossRefGoogle Scholar
  78. Lakin-Thomas PL (2006) Transcriptional feedback oscillators: maybe, maybe not. J Biol Rhythms 21(2):83–92PubMedCrossRefGoogle Scholar
  79. Lamia KA et al (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326(5951):437–440PubMedCrossRefGoogle Scholar
  80. Leak RK, Card JP, Moore RY (1999) Suprachiasmatic pacemaker organization analyzed by viral transynaptic transport. Brain Res 819(1–2):23–32PubMedCrossRefGoogle Scholar
  81. Lee J et al (2008) Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol 28(19):6056–6065PubMedCrossRefGoogle Scholar
  82. Lee Y et al (2010) Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. J Cell Sci 123(Pt 20):3547–3557PubMedCrossRefGoogle Scholar
  83. Lee HM et al (2011) The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1. Proc Natl Acad Sci USA 108(39): 16451–16456PubMedCrossRefGoogle Scholar
  84. Legewie S et al (2008) Recurrent design patterns in the feedback regulation of the mammalian signalling network. Mol Syst Biol 4:190PubMedCrossRefGoogle Scholar
  85. Lenz P, Sogaard-Andersen L (2011) Temporal and spatial oscillations in bacteria. Nat Rev Microbiol 9(8):565–577PubMedCrossRefGoogle Scholar
  86. Levi F, Schibler U (2007) Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol 47:593–628PubMedCrossRefGoogle Scholar
  87. Long MA et al (2005) Electrical synapses coordinate activity in the suprachiasmatic nucleus. Nat Neurosci 8(1):61–66PubMedCrossRefGoogle Scholar
  88. Lowrey PL et al (2000) Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288(5465):483–492PubMedCrossRefGoogle Scholar
  89. Lundkvist GB et al (2005) A calcium flux is required for circadian rhythm generation in mammalian pacemaker neurons. J Neurosci 25(33):7682–7686PubMedCrossRefGoogle Scholar
  90. Ma D, Panda S, Lin JD (2011) Temporal orchestration of circadian autophagy rhythm by C/EBPbeta. EMBO J 30(22):4642–4651PubMedCrossRefGoogle Scholar
  91. Maier B et al (2009) A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock. Genes Dev 23(6):708–718PubMedCrossRefGoogle Scholar
  92. Martinek S et al (2001) A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105(6):769–779PubMedCrossRefGoogle Scholar
  93. Maywood ES et al (2006) Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol 16(6):599–605PubMedCrossRefGoogle Scholar
  94. Maywood ES et al (2011) A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. Proc Natl Acad Sci USA 108(34):14306–14311PubMedCrossRefGoogle Scholar
  95. McGlincy NJ et al (2012) Regulation of alternative splicing by the circadian clock and food related cues. Genome Biol 13(6):R54PubMedCrossRefGoogle Scholar
  96. Meng QJ et al (2008) Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58(1): 78–88PubMedCrossRefGoogle Scholar
  97. Meng QJ et al (2010) Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci USA 107(34):15240–15245PubMedCrossRefGoogle Scholar
  98. Merrow M, Roenneberg T (2001) Circadian clocks: running on redox. Cell 106(2):141–143PubMedCrossRefGoogle Scholar
  99. Merrow M, Brunner M, Roenneberg T (1999) Assignment of circadian function for the Neurospora clock gene frequency. Nature 399(6736):584–586PubMedCrossRefGoogle Scholar
  100. Metallo CM, Vander Heiden MG (2011) Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev 24(24):2717–2722CrossRefGoogle Scholar
  101. Minami Y et al (2009) Measurement of internal body time by blood metabolomics. Proc Natl Acad Sci USA 106(24):9890–9895PubMedCrossRefGoogle Scholar
  102. Montenarh M (2010) Cellular regulators of protein kinase CK2. Cell Tissue Res 342(2):139–146PubMedCrossRefGoogle Scholar
  103. Muck W et al (2000) Pharmacokinetics of cerivastatin when administered under fasted and fed conditions in the morning or evening. Int J Clin Pharmacol Ther 38(6):298–303PubMedGoogle Scholar
  104. Musiek ES, FitzGerald GA (2013) Molecular clocks in pharmacology. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  105. Nakahata Y et al (2008) The NAD+−dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134(2):329–340PubMedCrossRefGoogle Scholar
  106. Nakajima et al (2005) Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308(5720):414–415Google Scholar
  107. Nelson DE et al (2004) Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 306(5696):704–708PubMedCrossRefGoogle Scholar
  108. Njus D et al (1976) Membranes and molecules in circadian systems. Fed Proc 35(12):2353–2357PubMedGoogle Scholar
  109. Noble D (2008) Claude Bernard, the first systems biologist, and the future of physiology. Exp Physiol 93(1):16–26PubMedCrossRefGoogle Scholar
  110. Noguchi T et al (2012) Fibroblast circadian rhythms of PER2 expression depend on membrane potential and intracellular calcium. Chronobiol Int 29(6):653–664PubMedCrossRefGoogle Scholar
  111. O’Neill JS, Reddy AB (2011) Circadian clocks in human red blood cells. Nature 469(7331): 498–503PubMedCrossRefGoogle Scholar
  112. O’Neill JS et al (2008) cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320(5878):949–953PubMedCrossRefGoogle Scholar
  113. O’Neill JS et al (2011) Circadian rhythms persist without transcription in a eukaryote. Nature 469(7331):554–558PubMedCrossRefGoogle Scholar
  114. Obrietan K et al (1999) Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274(25):17748–17756PubMedCrossRefGoogle Scholar
  115. Ortiz-Tudela E, Mteyrek A, Ballesta A, Innominato PF, Lévi F (2013) Cancer chronotherapeutics: experimental, theoretical and clinical aspects. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  116. Partch CL et al (2006) Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5. Proc Natl Acad Sci USA 103(27):10467–10472PubMedCrossRefGoogle Scholar
  117. Pennartz CM et al (2002) Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 416(6878):286–290PubMedCrossRefGoogle Scholar
  118. Pittendrigh CS, Caldarola PC, Cosbey ES (1973) A differential effect of heavy water on temperature-dependent and temperature-compensated aspects of circadian system of Drosophila pseudoobscura. Proc Natl Acad Sci USA 70(7):2037–2041PubMedCrossRefGoogle Scholar
  119. Powanda MC, Wannemacher RW Jr (1970) Evidence for a linear correlation between the level of dietary tryptophan and hepatic NAD concentration and for a systematic variation in tissue NAD concentration in the mouse and the rat. J Nutr 100(12):1471–1478PubMedGoogle Scholar
  120. Radha E et al (1985) Glutathione levels in human platelets display a circadian rhythm in vitro. Thromb Res 40(6):823–831PubMedCrossRefGoogle Scholar
  121. Ralph MR et al (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247(4945):975–978PubMedCrossRefGoogle Scholar
  122. Ramsey KM et al (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324(5927):651–654PubMedCrossRefGoogle Scholar
  123. Reddy AB (2013) Genome-wide analyses of circadian systems. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  124. Reddy AB, O’Neill JS (2010) Healthy clocks, healthy body, healthy mind. Trends Cell Biol 20(1): 36–44PubMedCrossRefGoogle Scholar
  125. Reddy AB et al (2005) Circadian clocks: neural and peripheral pacemakers that impact upon the cell division cycle. Mutat Res 574(1–2):76–91PubMedGoogle Scholar
  126. Reddy AB et al (2006) Circadian orchestration of the hepatic proteome. Curr Biol 16(11): 1107–1115PubMedCrossRefGoogle Scholar
  127. Reddy AB et al (2007) Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology 45(6):1478–1488PubMedCrossRefGoogle Scholar
  128. Reischl S et al (2007) Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics. J Biol Rhythms 22(5):375–386PubMedCrossRefGoogle Scholar
  129. Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418(6901): 935–941PubMedCrossRefGoogle Scholar
  130. Robertson JB et al (2008) Real-time luminescence monitoring of cell-cycle and respiratory oscillations in yeast. Proc Natl Acad Sci USA 105(46):17988–17993PubMedCrossRefGoogle Scholar
  131. Robles MS, Mann M (2013) Proteomic approaches in circadian biology. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  132. Roenneberg T, Merrow M (2002) “What watch?…such much!” Complexity and evolution of circadian clocks. Cell Tissue Res 309(1):3–9PubMedCrossRefGoogle Scholar
  133. Roenneberg T, Remi J, Merrow M (2010) Modeling a circadian surface. J Biol Rhythms 25(5): 340–9PubMedCrossRefGoogle Scholar
  134. Ruoff P, Zakhartsev M, Westerhoff HV (2007) Temperature compensation through systems biology. FEBS J 274(4):940–950PubMedCrossRefGoogle Scholar
  135. Rutter J et al (2001) Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293(5529):510–514PubMedCrossRefGoogle Scholar
  136. Sahar S, Sassone-Corsi P (2013) The epigenetic language of circadian clocks. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  137. Sahar S et al (2010) Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS One 5(1):e8561PubMedCrossRefGoogle Scholar
  138. Salazar C, Hofer T (2009) Multisite protein phosphorylation–from molecular mechanisms to kinetic models. FEBS J 276(12):3177–3198PubMedCrossRefGoogle Scholar
  139. Sathyanarayanan S et al (2004) Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A. Cell 116(4):603–615PubMedCrossRefGoogle Scholar
  140. Schmutz I et al (2011) Protein phosphatase 1 (PP1) is a post-translational regulator of the mammalian circadian clock. PLoS One 6(6):e21325PubMedCrossRefGoogle Scholar
  141. Schulz P, Steimer T (2009) Neurobiology of circadian systems. CNS Drugs 23(Suppl 2):3–13PubMedCrossRefGoogle Scholar
  142. Schweizer FE, Ryan TA (2006) The synaptic vesicle: cycle of exocytosis and endocytosis. Curr Opin Neurobiol 16(3):298–304PubMedCrossRefGoogle Scholar
  143. Sethi JK, Vidal-Puig A (2011) Wnt signalling and the control of cellular metabolism. Biochem J 427(1):1–17CrossRefGoogle Scholar
  144. Shibata S et al (1984) The role of calcium ions in circadian rhythm of suprachiasmatic nucleus neuron activity in rat hypothalamic slices. Neurosci Lett 52(1–2):181–184PubMedCrossRefGoogle Scholar
  145. Siepka SM et al (2007) Circadian mutant overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129(5):1011–1023PubMedCrossRefGoogle Scholar
  146. Skene DJ, Arendt J (2006) Human circadian rhythms: physiological and therapeutic relevance of light and melatonin. Ann Clin Biochem 43(Pt 5):344–353PubMedCrossRefGoogle Scholar
  147. Slat E, Freeman GM Jr, Herzog ED (2013) The clock in the brain: neurons, glia and networks in daily rhythms. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergCrossRefGoogle Scholar
  148. Spengler ML et al (2009) A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation. Cell Cycle 8(24):4138–4146PubMedCrossRefGoogle Scholar
  149. Suter DM et al (2011) Mammalian genes are transcribed with widely different bursting kinetics. Science 332(6028):472–474PubMedCrossRefGoogle Scholar
  150. Tahara Y et al (2012) In vivo monitoring of peripheral circadian clocks in the mouse. Curr Biol 22(11):1029–1034PubMedCrossRefGoogle Scholar
  151. Tischkau SA et al (2003) Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J Biol Chem 278(2):718–723PubMedCrossRefGoogle Scholar
  152. Tsuchiya Y et al (2009) Involvement of the protein kinase CK2 in the regulation of mammalian circadian rhythms. Sci Signal 2(73):ra26PubMedCrossRefGoogle Scholar
  153. Ueda HR et al (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37(2):187–192PubMedCrossRefGoogle Scholar
  154. Ukai H, Ueda HR (2010) Systems biology of mammalian circadian clocks. Annu Rev Physiol 72: 579–603PubMedCrossRefGoogle Scholar
  155. Um JH et al (2007) Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. J Biol Chem 282(29):20794–20798PubMedCrossRefGoogle Scholar
  156. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033PubMedCrossRefGoogle Scholar
  157. VanderLeest HT et al (2007) Seasonal encoding by the circadian pacemaker of the SCN. Curr Biol 17(5):468–473PubMedCrossRefGoogle Scholar
  158. Virshup DM et al (2007) Reversible protein phosphorylation regulates circadian rhythms. Cold Spring Harb Symp Quant Biol 72:413–420PubMedCrossRefGoogle Scholar
  159. Vitaterna MH et al (1994) Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264(5159):719–725PubMedCrossRefGoogle Scholar
  160. Vitaterna MH et al (1999) Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc Natl Acad Sci USA 96(21):12114–12119PubMedCrossRefGoogle Scholar
  161. Welsh DK et al (2004) Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol 14(24): 2289–2295PubMedCrossRefGoogle Scholar
  162. Welsh DK, Takahashi JS, Kay SA (2010) Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol 72:551–577PubMedCrossRefGoogle Scholar
  163. Westermarck J (2010) Regulation of transcription factor function by targeted protein degradation: an overview focusing on p53, c-Myc, and c-Jun. Methods Mol Biol 647:31–36PubMedCrossRefGoogle Scholar
  164. Woolum JC (1991) A re-examination of the role of the nucleus in generating the circadian rhythm in Acetabularia. J Biol Rhythms 6(2):129–136PubMedCrossRefGoogle Scholar
  165. Wu JQ, Snyder M (2008) RNA polymerase II stalling: loading at the start prepares genes for a sprint. Genome Biol 9(5):220PubMedCrossRefGoogle Scholar
  166. Xiao B et al (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472(7342): 230–233PubMedCrossRefGoogle Scholar
  167. Xu C, Kim NG, Gumbiner BM (2009) Regulation of protein stability by GSK3 mediated phosphorylation. Cell Cycle 8(24):4032–4039PubMedCrossRefGoogle Scholar
  168. Yamaguchi S et al (2000) The 5' upstream region of mPer1 gene contains two promoters and is responsible for circadian oscillation. Curr Biol 10(14):873–876PubMedCrossRefGoogle Scholar
  169. Yamaguchi S et al (2003) Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302(5649):1408–1412PubMedCrossRefGoogle Scholar
  170. Yang Y et al (2004) Distinct roles for PP1 and PP2A in the Neurospora circadian clock. Genes Dev 18(3):255–260PubMedCrossRefGoogle Scholar
  171. Yin L et al (2006) Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science 311(5763):1002–1005PubMedCrossRefGoogle Scholar
  172. Yin L et al (2007) Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318(5857):1786–1789PubMedCrossRefGoogle Scholar
  173. Yoo SH et al (2004) PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101(15): 5339–5346PubMedCrossRefGoogle Scholar
  174. Zhang EE et al (2009) A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell 139(1):199–210PubMedCrossRefGoogle Scholar
  175. Zhang EE et al (2010) Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16(10):1152–1156PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • John S. O’Neill
    • 1
    Email author
  • Elizabeth S. Maywood
    • 2
  • Michael H. Hastings
    • 2
  1. 1.Department of Clinical NeurosciencesUniversity of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s HospitalCambridgeUK
  2. 2.Division of NeurobiologyMedical Research Council Laboratory of Molecular BiologyCambridgeUK

Personalised recommendations