Regulation of the Circadian Oscillator in Xenopus Retinal Photoreceptors by Protein Kinases Sensitive to the Stress-activated Protein Kinase Inhibitor, SB 203580

Hasegawa, Minoru; Cahill, Gregory M.

doi:10.1074/jbc.m401389200

Cited by 23 publications

(20 citation statements)

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“…Following inhibition of p38 MAPK activation, using its inhibitor SB203580, Hayashi et al (2003) found the free-running period of the rhythm of melatonin release in cultured chick pineal cells extended from 24.0±0.3 h to 28.7±1.1 h. They also reported that a 4 h-pulse of SB203580 given during the subjective day could delay the phase of the melatonin release rhythm. SP600125 could also dose-dependently delay the phase of the rhythm of melatonin release from Xenopus photoreceptor layers (Hasegawa and Cahill, 2004). The similar effects of SB203580 and SP600125 might suggest that p38 MAPK and JNK are both involved in the regulation of the circadian molecular clockwork.…”

Section: Discussionmentioning

confidence: 74%

“…The related p38 MAPK and ERK subfamilies activation were found rhythmic in tissues containing circadian oscillators. First, p38 MAPK phosphorylation levels oscillate in the rat and chick pineal gland where these kinases have been shown to control the period and phase of circadian rhythms (Hayashi et al, 2003;Hasegawa and Cahill, 2004). Second, daily and circadian rhythms of ERK activations occur respectively in the rat pineal gland (Ho et al, 2003), and in both Syrian hamster and mouse SCN (Obrietan et al, 1998;Pizzio et al, 2003).…”

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confidence: 99%

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c-Jun N-terminal kinase inhibitor SP600125 modulates the period of mammalian circadian rhythms

et al. 2007

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Circadian rhythms are endogenous cycles with periods close to, but not exactly equal to, 24 h. In mammals, circadian rhythms are generated in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as several peripheral cell types, such as fibroblasts. Protein kinases are key regulators of the circadian molecular machinery. We investigated the role of the c-Jun N-terminal kinases (JNK), which belong to the mitogen-activated protein kinases family, in the regulation of circadian rhythms. In rat-1 fibroblasts, the p46 kDa, but not the p54 kDa, isoforms of JNK expressed circadian rhythms in phosphorylation. The JNK-inhibitor SP600125 dose-dependently extended the period of Period1-luciferase rhythms in rat-1 fibroblasts from 24.23±0.17-31.48±0.07 h. This treatment also dose-dependently delayed the onset of the bioluminescence rhythms. The effects of SP600125 on explant cultures from Period1-luciferase transgenic mice and Period2 Luciferase knockin mice appeared tissue-specific. SP600125 lengthened the period in SCN, pineal gland, and lung explants in Period1-luciferase and Period2 Luciferase mice. However, in the kidneys circadian rhythms were abolished in Period1-luciferase, while circadian rhythms were not affected by SP600125 treatment in Period2 Luciferase mice. Valproic acid, already known to affect period length, enhanced JNK phosphorylation and, as predicted, shortened the period of the Period1-bioluminescence rhythms in rat-1 fibroblasts. In conclusion, our results showed that SP600125 treatment, as well as valproic acid, alters JNK phosphorylation levels, and modulates the period length in various tissues. We conclude that JNK phosphorylation levels may help to set the period length of mammalian circadian rhythms. Keywords SCN; peripheral oscillators; Period genes; valproic acid; real time bioluminescence monitoringDeveloped through evolution to adjust to environmental conditions, self-sustained circadian oscillators generate daily fluctuations in behavior and physiology with a period of approximately 24 h. The study of the mammalian circadian clock at molecular levels has progressed dramatically over the past decade (Fukuhara and Tosini, 2003;Schibler et al., 2003;Gachon et al., 2004). In mammals, the central circadian clock is localized to the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes circadian events within the body. Peripheral circadian clocks have been found in many types of cells and tissues, e.g. fibroblasts, pineal gland, heart, liver, kidney, lung, and so on. Sustained circadian rhythm can be generated not only in a SCN neuron, but also in a fibroblast and other tissues and organs. Numerous studies of the molecular clock mechanism have suggested that these circadian pacemakers consist of transcriptional/translational autoregulatory feedback loops of several clock gene products (Hastings and Herzog, 2004;Ko and Takahashi, 2006). The stability of clock proteins, regulated through phosphorylation and dephosphorylation via protein kinases and phosphatases, is ...

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Section: Discussionmentioning

confidence: 74%

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confidence: 99%

c-Jun N-terminal kinase inhibitor SP600125 modulates the period of mammalian circadian rhythms

et al. 2007

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“…The ϳ25 mV hyperpolarizing shift in V 1/2 caused by inhibition of p38 MAPK activity suggests that constitutive (i.e., tonically active) intracellular p38 MAPK activity is a major determinant of normal h-channel properties. A similar phenomenon has been shown for tyrosine kinases in the maintenance of resting CNG (cyclic nucleotidegated) channel properties (Kramer and Molokanova, 2001), and there is evidence in cell types as diverse as Xenopus oocytes, human embryonic kidney cells, and rat hepatocytes that constitutive p38 MAPK activity regulates a variety of signaling pathways (Feranchak et al, 2001;Hasegawa and Cahill, 2004;Samuvel et al, 2005). The present results, however, do not show whether p38 MAPK phosphorylates specific residues on the HCN protein, leaving open the possibility that downstream effectors of p38 MAPK mediate its actions on I h .…”

Section: Discussionmentioning

confidence: 95%

Modulation of h-Channels in Hippocampal Pyramidal Neurons by p38 Mitogen-Activated Protein Kinase

2006

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Hyperpolarization-activated cyclic nucleotide-gated ion channels (h-channels; I h ; HCN) modulate intrinsic excitability in hippocampal and neocortical pyramidal neurons, among others. Whereas I h mediated by the HCN2 isoform is regulated by cAMP, there is little known about kinase modulation of I h , especially for the HCN1 isoform predominant in pyramidal neurons. We used a computational method to identify a novel kinase modulator of h-channels, p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK in hippocampal pyramidal neurons caused a ϳ25 mV hyperpolarization of I h voltage-dependent activation. This downregulation of I h produced hyperpolarization of resting potential, along with increased input resistance and temporal summation of excitatory inputs. Activation of p38 MAPK caused a ϳ11 mV depolarizing shift in I h activation, along with depolarized resting potential, and decreased input resistance and temporal summation. Inhibition of related MAPKs, ERK1/2 (extracellular signal-related kinase 1/2) and JNK (c-Jun N-terminal kinase), produced no effect on I h . These results show that p38 MAPK is a strong modulator of h-channel biophysical properties and may deserve additional exploration as a link between altered I h and pathological conditions such as epilepsy.

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“…In a Xenopus photoreceptor model of circadian rhythmicity, administration of SB203580, a nonselective inhibitor of CKI, reset the circadian pattern of melatonin secretion as a function of phase (Hasegawa and Cahill, 2004). CKI-7, a more selective CKI inhibitor, reduced PER degradation, delayed the nuclear entry of the protein, and lengthened the duration of nuclear residence (Miyazaki et al, 2004).…”

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An Inhibitor of Casein Kinase Iϵ Induces Phase Delays in Circadian Rhythms under Free-Running and Entrained Conditions

Badura

Swanson²,

Adamowicz³

et al. 2007

J Pharmacol Exp Ther

155

185

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Casein kinase I (CKI) is an essential component of the biological clock, phosphorylating PER proteins, and in doing so regulating their turnover and nuclear entry in oscillator cells of the suprachiasmatic nucleus (SCN). Although hereditary decreases in PER phosphorylation have been well characterized, little is known about the consequences of acute enzyme inhibition by pharmacological means. A novel reagent, 4-[3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamine (PF-670462), proved to be both a potent (IC 50 ϭ 7.7 Ϯ 2.2 nM) and selective (Ͼ30-fold with respect to 42 additional kinases) inhibitor of CKI in isolated enzyme preparations; in transfected whole cell assays, it caused a concentrationrelated redistribution of nuclear versus cytosolic PER. When tested in free-running animals, 50 mg/kg s.c. PF-670462 produced robust phase delays when dosed at circadian time (CT)9 (Ϫ1.97 Ϯ 0.17 h). Entrained rats dosed in normal light-dark (LD) and then released to constant darkness also experienced phase delays that were dose-and time of dosing-dependent. PF-670462 yielded only phase delays across the circadian cycle with the most sensitive time at CT12 when PER levels are near their peak in the SCN. Most importantly, these druginduced phase delays persisted in animals entrained and maintained in LD throughout the entire experiment; re-entrainment to the prevailing LD required days in contrast to the rapid elimination of the drug (t 1/2 ϭ 0.46 Ϯ 0.04 h). Together, these results suggest that inhibition of CKI yields a perturbation of oscillator function that forestalls light as a zeitgeber, and they demonstrate that pharmacological tools such as PF-670462 may yield valuable insight into clock function.Circadian behavior is mediated by a timed sequence of intracellular events, genomic in nature, occurring in mammals within so-called pacemaker cells of the suprachiasmatic nucleus (SCN) (Antle and Silver, 2005). Here, rhythmicity relies on a common theme of precisely regulated gene transcription and translation as a means to perpetuate cycling, and in doing so, to dictate the timing of downstream events (Reppert and Weaver, 2001; for review, see Schibler, 2006, among others). Clock-related proteins rise and fall in concentration as a consequence of nuclear and cytosolic feedback loops, adjusted daily to maintain reproducible cycling timed at roughly 24-h intervals. Light is the primary zeitgeber, or "time-giver", in this process, and its actions on loop dynamics are thought to comprise the most important external influence on pacemaker function.In its simplest conception, the oscillations of the clock can run using four genes, Period (Per1, Per2) and Cryptochrome (Cry1, Cry2), that are activated in early circadian day by heterodimeric complexes of CLOCK and BMAL1 (Griffin et al., 1999;Kume et al., 1999;Cermakian and Boivin, 2003). Translated PER partners in the cytoplasm with CRY, the resultant heterodimer, readily gaining nuclear entry and opposing activation by Clock and BMAL1. A feedback loop is...

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Regulation of the Circadian Oscillator in Xenopus Retinal Photoreceptors by Protein Kinases Sensitive to the Stress-activated Protein Kinase Inhibitor, SB 203580

Cited by 23 publications

References 50 publications

c-Jun N-terminal kinase inhibitor SP600125 modulates the period of mammalian circadian rhythms

c-Jun N-terminal kinase inhibitor SP600125 modulates the period of mammalian circadian rhythms

Modulation of h-Channels in Hippocampal Pyramidal Neurons by p38 Mitogen-Activated Protein Kinase

An Inhibitor of Casein Kinase Iϵ Induces Phase Delays in Circadian Rhythms under Free-Running and Entrained Conditions

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