MODEL1012080000
type: SBMLModel
area units: area
reaction: 814245
species: 812849
parameter: 812949
species: 812660
reaction: 813561
reaction: 814304
parameter: 813105
species: 812810
curated: false
time units: time
parameter: 812875
parameter: 813177
species: 812758
reaction: 814712
compartment: 812636
parameter: 813081
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species: 812696
species: 812708
parameter: 812888
parameter: 813285
parameter: 812985
notes: 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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parameter: 813141
parameter: 813129
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reaction: 813345
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reaction: 814784
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parameter: 813189
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reaction: 813633
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parameter: 813069
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reaction: 813849
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length unit: length
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reaction: 813297
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parameter: 813261
parameter: 812961
reaction: 813801
parameter: 813117
volume units: volume
reaction: 814065
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species: 812823
is described by: http://identifiers.org/pubmed/22735336
parameter: 813237
parameter: 813057
name: Heitzler2012_GPCRsignalling

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fast: false
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812823
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813105
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812810
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812875
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813177
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812758
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814724
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813081
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813213
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constant: false
value: 0.478865092
name: GRK23_si

812888
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value: 0.0178
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813285
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value: 7.20901786
name: nPKC

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value: 3.04
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813141
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name: G_a

812900
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814520
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814532
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814784
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814808
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813009
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813021
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813189
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812684
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813429
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813453
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813441
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812925
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813249
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name: P0_a_Ro

813093
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812937
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813069
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813897
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813165
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814580
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kinetic law: 814628
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814604
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813045
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813201
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constant: false
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name: GRK56

814640
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814412
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813273
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812973
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813261
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813117
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814065
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813525
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813513
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813033
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