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
Krishna Kumar Tiwari, Eric Reiter

Metadata information

is
BioModels Database MODEL1012080000
BioModels Database MODEL1012080000
hasTaxon
Taxonomy Homo sapiens
isInstanceOf
Gene Ontology transmembrane receptor protein serine/threonine kinase signaling pathway
Taxonomy Homo sapiens
Brenda Tissue Ontology kidney
BioModels Database MODEL1012080000
occursIn
Brenda Tissue Ontology kidney

Curation status
Curated

Tags
Name Description Size Actions

Model files

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

Additional files

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


Species
Species Initial Concentration/Amount
HR

P01019; P30556
0.08 mol
Gp

P63092
56.99 mol
ERK

P27361
4.243 mol
Reactions
Reactions Rate Parameters
(Gp + HR) => (Gp_a + HR)

([P63092] + [P01019; P30556]) => ([Guanine nucleotide-binding protein G(s) subunit alpha isoforms short; active] + [P01019; P30556])
compartmentOne*k2*G*HR/compartmentOne

compartmentOne*k2*[P63092]*[P01019; P30556]/compartmentOne
k2 = 7.6
(HR) => (HR-P1)

([P01019; P30556]) => ([P30556; P01019; phosphorylated])
compartmentOne*k10*GRK23*HR/compartmentOne

compartmentOne*k10*GRK23*[P01019; P30556]/compartmentOne
GRK23 = 0.899447579; k10 = 2.27
(HR-P1-b-arrestin1) => (b-arrestin1 + HR)

([P30556; P49407; P01019; phosphorylated]) => ([P49407] + [P01019; P30556])
compartmentOne*k15*Hbarr1RP1/compartmentOne

compartmentOne*k15*[P30556; P49407; P01019; phosphorylated]/compartmentOne
k15 = 6.54E-5
(HR-P1-b-arrestin2) => (b-arrestin2 + HR)

([P01019; P30556; Beta-arrestin-2; phosphorylated]) => ([Beta-arrestin-2] + [P01019; P30556])
compartmentOne*k16*Hbarr2RP1/compartmentOne

compartmentOne*k16*[P01019; P30556; Beta-arrestin-2; phosphorylated]/compartmentOne
k16 = 0.0723
(HR) => (HR-P2)

([P01019; P30556]) => ([P01019; P30556; phosphorylated])
compartmentOne*k18*GRK56*HR/compartmentOne

compartmentOne*k18*GRK56*[P01019; P30556]/compartmentOne
k18 = 0.59; GRK56 = 1.5180818
(HR-P2) => (HR)

([P01019; P30556; phosphorylated]) => ([P01019; P30556])
compartmentOne*k17*HRP2/compartmentOne

compartmentOne*k17*[P01019; P30556; phosphorylated]/compartmentOne
k17 = 0.0665
(b-arrestin2 + HR) => (HR_b-arrestin2)

([Beta-arrestin-2] + [P01019; P30556]) => ([P01019; P30556; Beta-arrestin-2])
compartmentOne*k19*barr2*HR/compartmentOne

compartmentOne*k19*[Beta-arrestin-2]*[P01019; P30556]/compartmentOne
k19 = 0.205
(HR_b-arrestin2) => (b-arrestin2 + HR)

([P01019; P30556; Beta-arrestin-2]) => ([Beta-arrestin-2] + [P01019; P30556])
compartmentOne*k23*HRbarr2/compartmentOne

compartmentOne*k23*[P01019; P30556; Beta-arrestin-2]/compartmentOne
k23 = 1.05
(Gp) => (Gp_a)

([P63092]) => ([Guanine nucleotide-binding protein G(s) subunit alpha isoforms short; active])
compartmentOne*k0*G/compartmentOne

compartmentOne*k0*[P63092]/compartmentOne
k0 = 3.11E-4
(Gp + HR-P1) => (Gp_a + HR-P1)

([P63092] + [P30556; P01019; phosphorylated]) => ([Guanine nucleotide-binding protein G(s) subunit alpha isoforms short; active] + [P30556; P01019; phosphorylated])
compartmentOne*k1*G*HRP1/compartmentOne

compartmentOne*k1*[P63092]*[P30556; P01019; phosphorylated]/compartmentOne
k1 = 0.0178
(Gp_a) => (Gp)

([Guanine nucleotide-binding protein G(s) subunit alpha isoforms short; active]) => ([P63092])
compartmentOne*k6*G_a/compartmentOne

compartmentOne*k6*[Guanine nucleotide-binding protein G(s) subunit alpha isoforms short; active]/compartmentOne
k6 = 5.0985
(ERK + PKC_a) => (Gp_pERK + PKC_a)

([P27361] + [P17252; PATO:0002354]) => ([P27361; phosphorylated] + [P17252; PATO:0002354])
compartmentOne*k5*ERK*PKC_a/compartmentOne

compartmentOne*k5*[P27361]*[P17252; PATO:0002354]/compartmentOne
k5 = 2.65
(Gp_pERK) => (ERK)

([P27361; phosphorylated]) => ([P27361])
compartmentOne*k9*GpERK/compartmentOne

compartmentOne*k9*[P27361; phosphorylated]/compartmentOne
k9 = 3.04
(ERK + HR_b-arrestin2) => (b_pERK + HR_b-arrestin2)

([P27361] + [P01019; P30556; Beta-arrestin-2]) => ([Mitogen-activated protein kinase 3; phosphorylated] + [P01019; P30556; Beta-arrestin-2])
compartmentOne*k21*ERK*HRbarr2/compartmentOne

compartmentOne*k21*[P27361]*[P01019; P30556; Beta-arrestin-2]/compartmentOne
k21 = 4.2E-4
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.