Lack of beta-arrestin signaling in the absence of active G proteins

Manuel Grundmann, Nicole Merten, Davide Malfacini, Asuka Inoue, Philip Preis, Katharina Simon, Nelly Rüttiger, Nicole Ziegler, Tobias Benkel, Nina Katharina Schmitt, Satoru Ishida, Ines Müller, Raphael Reher, Kouki Kawakami, Ayumi Inoue, Ulrike Rick, Toni Kühl, Diana Imhof, Junken Aoki, Gabriele M. KönigCarsten Hoffmann, Jesus Gomeza, Jürgen Wess, Evi Kostenis

Research output: Contribution to journalArticlepeer-review

188 Citations (Scopus)


G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of "zero functional G" at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o. Together with HEK293 cells lacking β-arrestins ("zero arrestin"), we systematically dissect G protein- from arrestin-driven signaling outcomes for a broad set of GPCRs. We use biochemical, biophysical, label-free whole-cell biosensing and ERK phosphorylation to identify four salient features for all receptors at "zero functional G": arrestin recruitment and internalization, but - unexpectedly - complete failure to activate ERK and whole-cell responses. These findings change our understanding of how GPCRs function and in particular of how they activate ERK1/2.

Original languageEnglish
Article number341
JournalNature communications
Issue number1
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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