ERK5 activation by Gq-coupled muscarinic receptors is independent of receptor internalization and β-arrestin recruitment
Entity
UAM. Departamento de Biología MolecularPublisher
Public Library of ScienceDate
2013-12-17Citation
10.1371/journal.pone.0084174
Plos One 8.12 (2013): e84174
ISSN
1932-6203 (online)DOI
10.1371/journal.pone.0084174Funded by
The study was funded by grants from Ministerio de Educación y Ciencia (SAF2011-23800), Fundación Ramón Areces, The Cardiovascular Diseases Network of Ministerio Sanidad y Consumo-Instituto Carlos III (RD12/0042/0012), Comunidad de Madrid (S-2011/BMD-2332) and Instituto de Salud Carlos III (PI11/00126).Project
Comunidad de Madrid. S2010/BMD-2332/INDISNETSubjects
Arrestins; Enzyme Activation; Fibroblasts; GTP-Binding Protein alpha Subunits; Phosphorylation; Biología y Biomedicina / BiologíaRights
© 2013 Sánchez-Fernández et al.Abstract
G-protein-coupled receptors (GPCRs) are known to activate both G protein- and β-arrestin-dependent signalling cascades. The initiation of mitogen-activated protein kinase (MAPK) pathways is a key downstream event in the control of cellular functions including proliferation, differentiation, migration and apoptosis. Both G proteins and β-arrestins have been reported to mediate context-specific activation of ERK1/2, p38 and JNK MAPKs. Recently, the activation of ERK5 MAPK by Gq-coupled receptors has been described to involve a direct interaction between Gαq and two novel effectors, PKCζ and MEK5. However, the possible contribution of β-arrestin towards this pathway has not yet been addressed. In the present work we sought to investigate the role of receptor internalization processes and β-arrestin recruitment in the activation of ERK5 by Gq-coupled GPCRs. Our results show that ERK5 activation is independent of M1 or M3 muscarinic receptor internalization. Furthermore, we demonstrate that phosphorylation-deficient muscarinic M1 and M3 receptors are still able to fully activate the ERK5 pathway, despite their reported inability to recruit β-arrestins. Indeed, the overexpression of Gαq, but not that of β-arrestin1 or β-arrestin2, was found to potently enhance ERK5 activation by GPCRs, whereas silencing of β-arrestin2 expression did not affect the activation of this pathway. Finally, we show that a β-arrestin-biased mutant form of angiotensin II (SII; Sar1-Ile4-Ile8 AngII) failed to promote ERK5 phosphorylation in primary cardiac fibroblasts, as compared to the natural ligand. Overall, this study shows that the activation of ERK5 MAPK by model Gq-coupled GPCRs does not depend on receptor internalization, β-arrestin recruitment or receptor phosphorylation but rather is dependent on Gαq-signalling
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Google Scholar:Sánchez-Fernández, Guzmán
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Cabezudo, Sofía
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García-Hoz, Carlota
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Tobin, Andrew B.
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Mayor Menéndez, Federico
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Ribas Núñez, Catalina
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