ERK5 activation by Gq-coupled muscarinic receptors is independent of receptor internalization and β-arrestin recruitment

PloS One
Guzmán Sánchez-FernándezCatalina Ribas

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, wa...Continue Reading

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Citations

Apr 1, 2015·Future Medicinal Chemistry·Zutao YuQianbin Li
Sep 4, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cédric BruléLaurent Prézeau
Feb 19, 2016·The Journal of Biological Chemistry·Guzmán Sánchez-FernándezCatalina Ribas
Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Daniela Volpato, Ulrike Holzgrabe

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