Characterization of serotonin-5-HTR1E signaling pathways and its role in cell survival
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223836 | GEO | 2023/06/21
REPOSITORIES: GEO
Similar Datasets
Project description:Chang2008 - ERK activation, hallucinogenic
drugs mediated signalling through serotonin receptors
This model is described in the article:
Towards a quantitative
representation of the cell signaling mechanisms of
hallucinogens: measurement and mathematical modeling of 5-HT1A
and 5-HT2A receptor-mediated ERK1/2 activation.
Chang CW, Poteet E, Schetz JA,
Gümü? ZH, Weinstein H.
Neuropharmacology 2009; 56 Suppl 1:
213-225
Abstract:
Through a multidisciplinary approach involving experimental
and computational studies, we address quantitative aspects of
signaling mechanisms triggered in the cell by the receptor
targets of hallucinogenic drugs, the serotonin 5-HT2A
receptors. To reveal the properties of the signaling pathways,
and the way in which responses elicited through these receptors
alone and in combination with other serotonin receptors'
subtypes (the 5-HT1AR), we developed a detailed mathematical
model of receptor-mediated ERK1/2 activation in cells
expressing the 5-HT1A and 5-HT2A subtypes individually, and
together. In parallel, we measured experimentally the
activation of ERK1/2 by the action of selective agonists on
these receptors expressed in HEK293 cells. We show here that
the 5-HT1AR agonist Xaliproden HCl elicited transient
activation of ERK1/2 by phosphorylation, whereas 5-HT2AR
activation by TCB-2 led to higher, and more sustained
responses. The 5-HT2AR response dominated the MAPK signaling
pathway when co-expressed with 5-HT1AR, and diminution of the
response by the 5-HT2AR antagonist Ketanserin could not be
rescued by the 5-HT1AR agonist. Computational simulations
produced qualitative results in good agreement with these
experimental data, and parameter optimization made this
agreement quantitative. In silico simulation experiments
suggest that the deletion of the positive regulators PKC in the
5-HT2AR pathway, or PLA2 in the combined 5-HT1A/2AR model
greatly decreased the basal level of active ERK1/2. Deletion of
negative regulators of MKP and PP2A in 5-HT1AR and 5-HT2AR
models was found to have even stronger effects. Under various
parameter sets, simulation results implied that the extent of
constitutive activity in a particular tissue and the specific
drug efficacy properties may determine the distinct dynamics of
the 5-HT receptor-mediated ERK1/2 activation pathways. Thus,
the mathematical models are useful exploratory tools in the
ongoing efforts to establish a mechanistic understanding and an
experimentally testable representation of hallucinogen-specific
signaling in the cellular machinery, and can be refined with
quantitative, function-related information.
This model is hosted on
BioModels Database
and identified by:
MODEL0975191032.
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.
2005-01-01 | MODEL0975191032 | BioModels
Project description:Chang2008 - ERK activation, hallucinogenic
drugs mediated signalling through serotonin receptors
This model is described in the article:
Towards a quantitative
representation of the cell signaling mechanisms of
hallucinogens: measurement and mathematical modeling of 5-HT1A
and 5-HT2A receptor-mediated ERK1/2 activation.
Chang CW, Poteet E, Schetz JA,
Gümü? ZH, Weinstein H.
Neuropharmacology 2009; 56 Suppl 1:
213-225
Abstract:
Through a multidisciplinary approach involving experimental
and computational studies, we address quantitative aspects of
signaling mechanisms triggered in the cell by the receptor
targets of hallucinogenic drugs, the serotonin 5-HT2A
receptors. To reveal the properties of the signaling pathways,
and the way in which responses elicited through these receptors
alone and in combination with other serotonin receptors'
subtypes (the 5-HT1AR), we developed a detailed mathematical
model of receptor-mediated ERK1/2 activation in cells
expressing the 5-HT1A and 5-HT2A subtypes individually, and
together. In parallel, we measured experimentally the
activation of ERK1/2 by the action of selective agonists on
these receptors expressed in HEK293 cells. We show here that
the 5-HT1AR agonist Xaliproden HCl elicited transient
activation of ERK1/2 by phosphorylation, whereas 5-HT2AR
activation by TCB-2 led to higher, and more sustained
responses. The 5-HT2AR response dominated the MAPK signaling
pathway when co-expressed with 5-HT1AR, and diminution of the
response by the 5-HT2AR antagonist Ketanserin could not be
rescued by the 5-HT1AR agonist. Computational simulations
produced qualitative results in good agreement with these
experimental data, and parameter optimization made this
agreement quantitative. In silico simulation experiments
suggest that the deletion of the positive regulators PKC in the
5-HT2AR pathway, or PLA2 in the combined 5-HT1A/2AR model
greatly decreased the basal level of active ERK1/2. Deletion of
negative regulators of MKP and PP2A in 5-HT1AR and 5-HT2AR
models was found to have even stronger effects. Under various
parameter sets, simulation results implied that the extent of
constitutive activity in a particular tissue and the specific
drug efficacy properties may determine the distinct dynamics of
the 5-HT receptor-mediated ERK1/2 activation pathways. Thus,
the mathematical models are useful exploratory tools in the
ongoing efforts to establish a mechanistic understanding and an
experimentally testable representation of hallucinogen-specific
signaling in the cellular machinery, and can be refined with
quantitative, function-related information.
This model is hosted on
BioModels Database
and identified by:
MODEL0975191032.
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.
2005-01-01 | MODEL0975191032 | BioModels
Project description:The protein tyrosine phosphatase PRL-1 (Gene Symbol: PTP4A1) has been identified as an important oncogene with roles in promoting cell proliferation, survival, migration, invasion, and metastasis. However, little is currently known about the signaling pathways through which it mediates its effects. Studies have shown a relationship between PRL-1 and the expression or activity levels of various molecules involved in integrin-mediated cell signaling. These integrin-responsive players can promote re-arrangements in the actin cytoskeleton that are central to cell motility, invasion, and metastasis. Therefore, to investigate the effects of PRL-1 overexpression in human embryonic kidney 293 (HEK293) cells, we used qRT-PCR to examine the expression levels of 184 genes which either were identified by microarray and proteomic analysis to be differentially expressed in response to PRL-1 or have known associations to integrin-mediated signaling, cytoskeletal remodeling, and/or cell motility. Total RNA was extracted from duplicate cultures of HEK293 cells stably overexpressing PRL-1 (HEK293-PRL-1) and HEK293 cells stably transfected with empty pcDNA4 vector (HEK293-Vector). Samples were analyzed using custom TaqMan Array 96-well Plates to examine the expression of 184 genes with known involvement in or association with signaling pathways related to integrin-mediated cell adhesion, cytoskeletal remodeling, and/or cell motility.
2013-07-30 | E-GEOD-42587 | biostudies-arrayexpress
Project description:Analysis of venticular myocardium from adenosine 2A receptors (A2AR) knockouts following LPS stimulation. Results provide insight into the molecular components of A2AR mediated protection, but also reveal pathogenetic components of endotoxemic myocarditis as a result of LPS exposure. These findings demonstrate that intrinsic A2AR activity exerts limited transcriptional effects in unstressed heart, modifying G-coupled cAMP/PKA signal paths. LPS-dependent injury and dysfunction is associated with profound up-regulation of inflammatory/immune processes, fibrotic and cell death paths, and NF-kB, Erk/MAPK and JAK/Stat signaling, with shifts in multiple determinants of cardiac contraction and survival. Intrinsic A2AR activity modulates key aspects of these inflammatory responses, involving MAPK, JAK/Stat and NF-kB signaling Total RNA obtained from adenosine 2A receptor knockout or wild-type murine ventricular myocardium that were treated for 24 hours with either saline or lipopolysaccharide (n=4/group).
2013-05-01 | E-GEOD-44363 | biostudies-arrayexpress
Project description:A deeper understanding of the regulation of G protein-coupled receptors (GPCRs) and their associated downstream cascades will provide critical insights into how these pathways shape human physiology and disease, and could yield novel therapeutic targets. Here, we validate and characterize RNA-binding motif 12 (Rbm12) as a repressor of GPCR/cAMP signaling. We established Rbm12 CRISPR KO HEK293 cells using two independent gRNAs and human iPSC-derived neurons (iNeuron) depleted of Rbm12 via CRISPR interference. Then, we performed basal gene expression profiling (HEK293) and basal + beta-2-adrenergic receptor induced (1 hour of 1 uM Isoproterenol) conditions (neurons).
2023-08-02 | GSE219195 | GEO
Project description:The multifunctional protein tyrosine phosphatase PRL-1 (Gene Symbol: PTP4A1) has been identified as an important oncogene with roles in promoting cell proliferation, survival, migration, invasion, and metastasis. However, little is currently known about the signaling pathways through which it mediates its effects. We used Affymetrix Human Genome U133 Plus 2.0 arrays to examine the global molecular changes of gene expression occurring in response to stable PRL-1 overexpression in human embryonic kidney 293 (HEK293) cells. Total RNA was extracted from triplicate cultures of HEK293 cells stably overexpressing PRL-1 (HEK293-PRL-1) and HEK293 cells stably transfected with empty pcDNA4 vector (HEK293-Vector). Samples were hybridized to Affymetrix HG U133 Plus 2.0 microarrays (1 array per sample for a total of 6 arrays). One of the arrays hybridized with a PRL-1 transfected sample was excluded after qRT-PCR demonstrated that this sample did not exhibit increased PRL-1 expression over the level of the empty vector controls. The remaining 2 HEK293-PRL-1 samples both expressed PRL-1 at least 2-fold higher than any of the 3 empty vector controls.
2013-07-30 | E-GEOD-42586 | biostudies-arrayexpress
Project description:This model is from the article:
Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling
Heitzler D, Durand G, Gallay N, Rizk A, Ahn S, Kim J, Violin JD, Dupuy L, Gauthier C, Piketty V, Crépieux P, Poupon A, Clément F, Fages F, Lefkowitz RJ, Reiter E. Mol Syst Biol.
2012; 8: 590. 22735336
,
Abstract:
Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β-arrestins, whose recruitment to the activated receptor is regulated by G protein-coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal-regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT(1A)R) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)-based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well-established function in the desensitization of G-protein activation, GRK2 exerts a strong negative effect on β-arrestin-dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2-dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT(1A)R, and HEK293 cells expressing other 7TMRs.
2024-09-02 | BIOMD0000000842 | BioModels
Project description:This gene array analysis shows that the transcriptome of HEK293, representing low-differentiated human embryonic kidney cells, cultured in presence of tRA and cAMP differentiating agents, is consistent with a genetic program relevant to kidney development Comparison of HEK293 cells grown in standard contitions or in presence of differentiating agents. Cells were seeded in 10 cm dishes, cultured for 3 days either in complete medium or in medium supplemented with tRA and cAMP, harvested, and spun down before RNA isolation. Comparative analysis allowed us to identify genes transcriptionally by tRA/cAMP.
2016-09-06 | E-GEOD-62722 | biostudies-arrayexpress
Project description:During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta-cells. However, the exact mechanisms by which the lactogenic hormones drive beta-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive beta-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in beta-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes. Analysis of poly(A)+ RNA from 3 biological replicates of pancreatic islets isolated from normal female and pregnant female mice
2010-07-01 | E-GEOD-21860 | biostudies-arrayexpress
Project description:The B cell receptor (BCR) signaling, required for the survival and maturation of B cells, is a major deregulated pathway in B cell lymphomas. Several mutations are known to enhance the tonic BCR signal in Burkitt lymphomas (BL) or to mimic an activated receptor in some diffuse large B cell lymphomas (DLBCL). While the proximal events and kinases of the BCR signaling are well studied, less is known about the interactions of downstream effector pathways. In order to reach a less abstract description of this pathway we decided to employ the Modular Response Analysis-based modelling approach STASNet on more directly connected phosphorylation data. Using a Luminex proteomics platform we measured the phosphorylation of fourteen signaling and effector proteins after activating the B cell receptor (BCR) signaling and/or using inhibitors directed against seven intracellular signaling molecules in two independent Burkitt lymphoma cells (BL-2, BL-41). Application of a novel two step STASNet modelling pipeline unveiled novel feedback and crosstalk structures in the BCR-driven signaling network, including a crosstalk from p38 which negatively regulates MEK/ERK-activity in the presence of active BCR. Using Western Blot measurements, we verified and further characterized the p38-MEK/ERK crosstalk and demonstrated that it is a general mechanism in BL cells. Global Tandem Mass Tag (TMT) phosphoproteomic analysis on BL-2 cells found PI3K to be a major mediator of B-cell receptor signaling and manifested the p38-ERK crosstalk directly on ERK phosphosites and indirectly on seven bona fide ERK targets. We also noticed that the BL-2-learned pathway network structure was transferable to perturbation data from closely related BL-41 cells. Moreover, - compared to a literature-derived network - the BL-2-developed predictive pathway proved also to be a better starting point for network development in cells with aberrant BCR signaling in two representative cell lines derived from Diffuse large B cells (HBL-1, OCI-LY3). This indicates that models trained on activated B-cells are highly informative to be transferred to closely related cancer signaling network.
2024-09-14 | PXD047709 | Pride