Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2012-06-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/msb.2012.22 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849388848385097728 |
|---|---|
| author | Domitille Heitzler Guillaume Durand Nathalie Gallay Aurélien Rizk Seungkirl Ahn Jihee Kim Jonathan D Violin Laurence Dupuy Christophe Gauthier Vincent Piketty Pascale Crépieux Anne Poupon Frédérique Clément François Fages Robert J Lefkowitz Eric Reiter |
| author_facet | Domitille Heitzler Guillaume Durand Nathalie Gallay Aurélien Rizk Seungkirl Ahn Jihee Kim Jonathan D Violin Laurence Dupuy Christophe Gauthier Vincent Piketty Pascale Crépieux Anne Poupon Frédérique Clément François Fages Robert J Lefkowitz Eric Reiter |
| author_sort | Domitille Heitzler |
| collection | DOAJ |
| description | 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 (AT1AR) 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 AT1AR, and HEK293 cells expressing other 7TMRs. |
| format | Article |
| id | doaj-art-36341ec006974a4487849a5c5291ac17 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2012-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-36341ec006974a4487849a5c5291ac172025-08-20T03:42:09ZengSpringer NatureMolecular Systems Biology1744-42922012-06-018111710.1038/msb.2012.22Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signalingDomitille Heitzler0Guillaume Durand1Nathalie Gallay2Aurélien Rizk3Seungkirl Ahn4Jihee Kim5Jonathan D Violin6Laurence Dupuy7Christophe Gauthier8Vincent Piketty9Pascale Crépieux10Anne Poupon11Frédérique Clément12François Fages13Robert J Lefkowitz14Eric Reiter15BIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsContraintes Team, INRIA Paris‐RocquencourtDepartment of Medicine, Duke University Medical Center, Howard Hughes Medical InstituteDepartment of Medicine, Duke University Medical Center, Howard Hughes Medical InstituteDepartment of Medicine, Duke University Medical Center, Howard Hughes Medical InstituteBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsSisyphe Team, INRIA Paris‐RocquencourtContraintes Team, INRIA Paris‐RocquencourtDepartment of Medicine, Duke University Medical Center, Howard Hughes Medical InstituteBIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des ComportementsAbstract 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 (AT1AR) 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 AT1AR, and HEK293 cells expressing other 7TMRs.https://doi.org/10.1038/msb.2012.22β‐arrestin7 transmembrane receptorsdynamical modelingG proteinsignal transduction |
| spellingShingle | Domitille Heitzler Guillaume Durand Nathalie Gallay Aurélien Rizk Seungkirl Ahn Jihee Kim Jonathan D Violin Laurence Dupuy Christophe Gauthier Vincent Piketty Pascale Crépieux Anne Poupon Frédérique Clément François Fages Robert J Lefkowitz Eric Reiter Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling Molecular Systems Biology β‐arrestin 7 transmembrane receptors dynamical modeling G protein signal transduction |
| title | Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling |
| title_full | Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling |
| title_fullStr | Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling |
| title_full_unstemmed | Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling |
| title_short | Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling |
| title_sort | competing g protein coupled receptor kinases balance g protein and β arrestin signaling |
| topic | β‐arrestin 7 transmembrane receptors dynamical modeling G protein signal transduction |
| url | https://doi.org/10.1038/msb.2012.22 |
| work_keys_str_mv | AT domitilleheitzler competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT guillaumedurand competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT nathaliegallay competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT aurelienrizk competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT seungkirlahn competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT jiheekim competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT jonathandviolin competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT laurencedupuy competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT christophegauthier competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT vincentpiketty competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT pascalecrepieux competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT annepoupon competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT frederiqueclement competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT francoisfages competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT robertjlefkowitz competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling AT ericreiter competinggproteincoupledreceptorkinasesbalancegproteinandbarrestinsignaling |