Heitzler2012 - GPCR signalling
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.
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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.
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Eric Reiter, Krishna Kumar Tiwari
Metadata information
isDescribedBy (2 statements)
Gene Ontology transmembrane receptor protein serine/threonine kinase signaling pathway
hasTaxon (1 statement)
isInstanceOf (4 statements)
Taxonomy Homo sapiens
Brenda Tissue Ontology kidney
BioModels Database MODEL1012080000
occursIn (1 statement)
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| MODEL1012080000.xml | SBML L2V4 representation of Heitzler2012_GPCRsignalling | 159.37 KB | Preview | Download |
Additional files |
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| 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
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Version: 5
- Submitted on: Nov 4, 2019 2:08:03 PM
- Submitted by: Krishna Kumar Tiwari
- With comment: Automatically added model identifier BIOMD0000000842
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Version: 2
- Submitted on: Jul 30, 2012 2:21:10 PM
- Submitted by: Eric Reiter
- With comment: Current version of Heitzler2012_GPCRsignalling
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Version: 1
- 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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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| HR P01019 ; P30556 |
0.08 mol |
| G Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
56.99 mol |
| PKC Protein kinase C alpha type |
8.842 mol |
| G a Guanine nucleotide-binding protein G(s) subunit alpha isoforms short ; active |
0.0 mol |
| HRP1 P30556 ; P01019 ; phosphorylated |
0.0 mol |
| Hbarr2RP2 P30556 ; P01019 ; Beta-arrestin-2 ; phosphorylated |
0.0 mol |
| PKC a Protein kinase C alpha type ; active |
0.002 mol |
| 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 |
(added: 04 Nov 2019, 14:07:10, updated: 04 Nov 2019, 14:07:10)