Heitzler2012 - GPCR signalling

  public model
Model Identifier
BIOMD0000000842
Short 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.

Format
SBML (L2V4)
Related Publication
  • 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
  • Molecular Systems Biology , 6/ 2012 , Volume 8 , pages: 590 , PubMed ID: 22735336
  • BIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements, Nouzilly, France.
  • 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.
Contributors
Submitter of the first revision: Eric Reiter
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Eric Reiter, Krishna Kumar Tiwari

Metadata information

is (2 statements)
BioModels Database MODEL1012080000
BioModels Database MODEL1012080000

isDescribedBy (2 statements)
hasTaxon (1 statement)
Taxonomy Homo sapiens

isInstanceOf (4 statements)
Gene Ontology transmembrane receptor protein serine/threonine kinase signaling pathway
Taxonomy Homo sapiens
Brenda Tissue Ontology kidney
BioModels Database MODEL1012080000

occursIn (1 statement)
Brenda Tissue Ontology kidney


Curation status
Curated

Tags

Connected external resources

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Model files

MODEL1012080000.xml SBML L2V4 representation of Heitzler2012_GPCRsignalling 159.37 KB Preview | Download

Additional files

MODEL1012080000-biopax2.owl Auto-generated BioPAX (Level 2) 48.57 KB Preview | Download
MODEL1012080000-biopax3.owl Auto-generated BioPAX (Level 3) 82.18 KB Preview | Download
MODEL1012080000.m Auto-generated Octave file 12.05 KB Preview | Download
MODEL1012080000.pdf Auto-generated PDF file 268.49 KB Preview | Download
MODEL1012080000.png Auto-generated Reaction graph (PNG) 527.94 KB Preview | Download
MODEL1012080000.sci Auto-generated Scilab file 8.99 KB Preview | Download
MODEL1012080000.sedml SEDML file for the model 25.33 KB Preview | Download
MODEL1012080000.svg Auto-generated Reaction graph (SVG) 77.65 KB Preview | Download
MODEL1012080000.vcml Auto-generated VCML file 46.99 KB Preview | Download
MODEL1012080000.xpp Auto-generated XPP file 9.43 KB Preview | Download
MODEL1012080000_url.cps Copasi 4.27 (built 217) file for the curated model 194.08 KB Preview | Download
MODEL1012080000_url.xml Original SBML file submitted by Author 29.18 KB Preview | Download
MODEL1012080000_urn.xml Auto-generated SBML file with URNs 30.15 KB Preview | Download

  • Model originally submitted by : Eric Reiter
  • Submitted: Dec 8, 2010 12:40:43 PM
  • Last Modified: Nov 4, 2019 2:08:03 PM
Revisions
  • Version: 5 public model Download this version
    • Submitted on: Nov 4, 2019 2:08:03 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Automatically added model identifier BIOMD0000000842
  • Version: 2 public model Download this version
    • Submitted on: Jul 30, 2012 2:21:10 PM
    • Submitted by: Eric Reiter
    • With comment: Current version of Heitzler2012_GPCRsignalling
  • Version: 1 public model Download this version
    • Submitted on: Dec 8, 2010 12:40:43 PM
    • Submitted by: Eric Reiter
    • With comment: Original import of MODEL1012080000.xml.origin

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Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
G + HR => G_a + HR; G, HR compartmentOne*k2*G*HR/compartmentOne k2 = 7.6
HRbarr2 => barr2 + HR; HRbarr2 compartmentOne*k23*HRbarr2/compartmentOne k23 = 1.05
G + HRP1 => G_a + HRP1; G, HRP1 compartmentOne*k1*G*HRP1/compartmentOne k1 = 0.0178
PKC_a => PKC; PKC_a compartmentOne*k8*PKC_a/compartmentOne k8 = 1.77
barr2 + HRP2 => Hbarr2RP2; barr2, HRP2 compartmentOne*k20*barr2*HRP2/compartmentOne k20 = 1.04
ERK + PKC_a => GpERK + PKC_a; ERK, PKC_a compartmentOne*k5*ERK*PKC_a/compartmentOne k5 = 2.65
barr2 + HRP1 => Hbarr2RP1; barr2, HRP1 compartmentOne*k12*barr2*HRP1/compartmentOne k12 = 2.59
Curator's comment:
(added: 04 Nov 2019, 14:07:10, updated: 04 Nov 2019, 14:07:10)
Model recreated using COPASI 4.27 (build217). Figure 5A and 5C is reproduced as per the setup given in the paper. Plot generated are from COPASI.