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ERK5 Activation by Gq-Coupled Muscarinic Receptors is Independent of Receptors Iternalization and beta-Arrestin Recruitment

AuthorsSánchez-Fernández, Guzmán ; Cabezudo, Sofía ; García-Hoz Jiménez, Carlota; Tobin, Andrew; Mayor Menéndez, Federico ; Ribas, Catalina
Issue Date17-Dec-2013
PublisherPublic Library of Science
CitationPLoS ONE 8(12): 9318- 9328 (2013)
AbstractThis work was funded by the Ministerio de Ciencia e Innovacion (MICINN) grants (SAF2008-00211; PIE- 200820I166), and a grant from the Spanish Comunidad de Madrid CCG08-CSIC/SAL-3464. 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 G αqand 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-Ile8AngII) 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.
Identifiersdoi: 10.1371/journal.pone.0084174
issn: 1932-6203
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