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Project description:Although a substantial number of hormones and drugs increase cellular cAMP levels, the global impact of cAMP and its major effector mechanism, protein kinase A (PKA), on gene expression is not known. Here we show that treatment of wild-type S49 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), a PKA-selective cAMP analog, alters the expression of ~4500 of ~13,600 unique genes. By contrast, gene expression was unaltered in Kin- S49 cells (that lack PKA) incubated with CPT-cAMP. Changes in mRNA and protein expression of several cell-cycle regulators accompanied cAMP-induced G1-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements (CRE) within 5 kb of transcriptional start sites, including the circadian clock gene Per1. Thus, cAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of CRE-containing genes and secondary networks that include the circadian clock.
2007-08-31 | E-GEOD-2413 | biostudies-arrayexpress
Project description:Abstract Although a substantial number of hormones and drugs increase cellular cAMP levels, the global impact of cAMP and its major effector mechanism, protein kinase A (PKA), on gene expression is not known. Here we show that treatment of wild-type S49 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), a PKA-selective cAMP analog, alters the expression of ~4500 of ~13,600 unique genes. By contrast, gene expression was unaltered in Kin– S49 cells (that lack PKA) incubated with CPT-cAMP. Changes in mRNA and protein expression of several cell-cycle regulators accompanied cAMP-induced G1-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements (CRE) within 5 kb of transcriptional start sites, including the circadian clock gene Per1. Thus, cAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of CRE-containing genes and secondary networks that include the circadian clock. Keywords: time-course
2005-04-15 | GSE2413 | GEO
Project description:Regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of circadian genes on cellular and molecular mechanisms that influnce synaptic plasticity and cognitive function remain to be identified. Here, we show that conditional deletion of the circadian gene Timeless in the adult forebrain leads to an impairment in working and fear memory in mice. These cognitive phenotypes were accompanied with LTP attenuation of hippocampal Schaffer-collateral synapses. We discovered TIMELESS protein acts as a transcriptional factor regulating phosphodiesterase 4B (PDE4B) expression. Through Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and fine-tune synaptic plasticity. Our data provide insights into the neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.
2023-04-17 | GSE208149 | GEO
Project description:Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced pre-awakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intra-hippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a five day oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity were misaligned with the natural light/dark circadian entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.
2023-02-12 | GSE224038 | GEO
Project description:Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced pre-awakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intra-hippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a five day oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity were misaligned with the natural light/dark circadian entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.
2023-02-12 | GSE223761 | GEO
Project description:Yapo2017- cAMP/PKA signalling in D1 dopamine receptor expressing medium-spiny neurons
This model is described in the article:
Detection of phasic dopamine
by D1 and D2 striatal medium spiny neurons.
Yapo C, Nair AG, Clement L, Castro
LR, Hellgren Kotaleski J, Vincent P.
J. Physiol. (Lond.) 2017 Aug; :
Abstract:
The phasic release of dopamine in the striatum determines
various aspects of reward and action selection, but the
dynamics of dopamine effect on intracellular signalling remains
poorly understood. We used genetically-encoded FRET biosensors
in striatal brain slices to quantify the effect of transient
dopamine on cAMP or PKA-dependent phosphorylation level, and
computational modelling to further explore the dynamics of this
signalling pathway. Medium-sized spiny neurons (MSNs), which
express either D1 or D2 dopamine receptors, responded to
dopamine by an increase or a decrease in cAMP, respectively.
Transient dopamine showed similar sub-micromolar efficacies on
cAMP in both D1 and D2 MSNs, thus challenging the commonly
accepted notion that dopamine efficacy is much higher on D2
than on D1 receptors. However, in D2 MSNs, the large decrease
in cAMP level triggered by transient dopamine did not translate
in a decrease in PKA-dependent phosphorylation level, owing to
the efficient inhibition of Protein Phosphatase 1 by DARPP-32.
Simulations further suggested that D2 MSNs can also operate in
a "tone-sensing" mode, allowing them to detect transient dips
in basal dopamine. Overall, our results show that D2 MSNs may
sense much more complex patterns of dopamine than previously
thought. This article is protected by copyright. All rights
reserved.
This model is hosted on
BioModels Database
and identified by:
MODEL1701170000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-08-16 | MODEL1701170000 | BioModels
Project description:Yapo2017 - A2AR/cAMP/PKA signalling in D2 dopamine receptor expressing medium-spiny neurons
This model is described in the article:
Detection of phasic dopamine
by D1 and D2 striatal medium spiny neurons.
Yapo C, Nair AG, Clement L, Castro
LR, Hellgren Kotaleski J, Vincent P.
J. Physiol. (Lond.) 2017 Aug; :
Abstract:
The phasic release of dopamine in the striatum determines
various aspects of reward and action selection, but the
dynamics of dopamine effect on intracellular signalling remains
poorly understood. We used genetically-encoded FRET biosensors
in striatal brain slices to quantify the effect of transient
dopamine on cAMP or PKA-dependent phosphorylation level, and
computational modelling to further explore the dynamics of this
signalling pathway. Medium-sized spiny neurons (MSNs), which
express either D1 or D2 dopamine receptors, responded to
dopamine by an increase or a decrease in cAMP, respectively.
Transient dopamine showed similar sub-micromolar efficacies on
cAMP in both D1 and D2 MSNs, thus challenging the commonly
accepted notion that dopamine efficacy is much higher on D2
than on D1 receptors. However, in D2 MSNs, the large decrease
in cAMP level triggered by transient dopamine did not translate
in a decrease in PKA-dependent phosphorylation level, owing to
the efficient inhibition of Protein Phosphatase 1 by DARPP-32.
Simulations further suggested that D2 MSNs can also operate in
a "tone-sensing" mode, allowing them to detect transient dips
in basal dopamine. Overall, our results show that D2 MSNs may
sense much more complex patterns of dopamine than previously
thought. This article is protected by copyright. All rights
reserved.
This model is hosted on
BioModels Database
and identified by:
MODEL1701170001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-08-16 | MODEL1701170001 | BioModels
Project description:Light controls control a vast array of biological processes, including cell and organelle motility, stress responses, organismal development and the entrainment of circadian rhythms, that maintain diurnal cycles of activity in organisms from cyanobacteria to humans. Recent studies indicate that a type of antioxidant and signaling proteins, peroxiredoxins, sustain circadian rhythms independent of characterized circadian pacemakers in organisms from all the three kingdoms of life, suggesting a role for H2O2 production in circadian clocks. Whereas many circadian clocks involve photosensitive pigments such as melanopsin and cryptochromes it is unclear whether peroxiredoxins can respond to light stimuli and how they interact with global signaling networks regulating e.g. clocks and aging, such as cyclic AMP (cAMP)/protein kinase A (PKA). In yeast, that lacks decidated photoreceptors, blue light induces cAMP-PKA-dependent, nuclear accumulation of a transcription factor, Msn2. However, the mechanism by which light represses pathway activity to stimulate Msn2 nuclear translocation is unknown. Here we identify increased H2O2–production via a conserved peroxisomal oxidase as the cause of light-induced Msn2 nuclear concentration. The H2O2 signal is transduced by the catalytic cysteines of the peroxiredoxin Tsa1 that relieve Msn2 from inhibitory PKA phosphorylation causing its nuclear accumulation. We propose that yeast senses light via H2O2 and a peroxiredoxin to inhibit cAMP/PKA activity and our data form a framework for the study of light responses in cells lacking dedicated light receptors and cAMP-controlled biological rhythms in multicellular organisms.
2018-07-03 | PXD001853 | Pride
Project description:The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brain’s central pacemaker, downstream “satellite clocks” may also regulate local functions based on the time of day. Within the dorsal hippocampus (DH), for example, local molecular oscillations may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1 (Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as Per1 oscillates in tandem with memory performance. We then show that local knockdown of Per1 within the DH has no effect on either the circadian rhythm or sleep behavior, although previous work has shown this manipulation impairs memory. Thus, Per1 may independently function within the DH to regulate memory in addition to its known role in regulating the circadian system within the SCN. Per1 may therefore exert local diurnal control over memory consolidation within the DH.
2024-01-12 | GSE222744 | GEO
Project description:There is growing appreciation that the feeling of well-being, alterations in mood and susceptibility to a variety of medical disorders depend on the proper expression of the master circadian clock and the synchrony among the other oscillators found in many peripheral tissues. To improve our understanding of the role of peripheral oscillators, an improved understanding of the molecular machinery sub-serving the circadian variation in gene expression is essential. Our long-term goal is to understand the molecular mechanisms that initiate circadian gene expression following external stimulation in the mammalian pineal gland. Are all or just some of the "circadian clock" genes induced by NE, cAMP, or cGMP? In this project we compare a series of gene expression patterns using DNA microarray in response to cAMP, cGMP and NE stimulation to understand why NE does not initiate circadian rhythms in the rat pineal gland. As a preliminary experiment we will compare gene expression 0, 1, and 4 h after start of chemical stimulation. A failure of NE to initiate circadian rhythms is due to failure of activation of certain "circadian clock" genes. We found that circadian rhythms are initiated by stimulation of cAMP or cGMP analogue in the rat pineal gland, while norepinephrine (NE) stimulation only moderately induce Period1 mRNA (one of "circadian clock" genes) 24 h after start of stimulation. From these results we hypothesize that external stimulation activates some "circadian clock" genes simultaneously, and that failure of circadian rhythm initiation following NE stimulation is due to insufficient "circadian clock" genes activations. Male rats of wistar strain are kept in 12h-12h light dark cycles at least for one week before start of experiments. Pineal glands are removed from animals and placed in the culture dish. Rat pineal glands are cultured for 3 days before chemical stimulation. On the day of experiment, the pineal cultures are stimulated using one of NE, cAMP and cGMP analogues for 1 or 4 h before harvest. The samples are immediately frozen and total RNA are extracted from each group which are from a pool of 8 pineal glands using Trizol reagent (Invitrogen). Concentrations of total RNA are determined using spectrophotometer, and six microgram of total RNA is aliquoted in each sample tube for further analysis. Since we already have Affymetrix Rat Genome U34A array GeneChips, we would like to send Chips as well as our total RNA samples. Experiment Overall Design: as above
2008-06-12 | E-GEOD-2865 | biostudies-arrayexpress