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. König, Carsten Hoffmann, Jesus Gomeza, Jürgen Wess and Evi Kostenis ()
Additional contact information
Manuel Grundmann: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Nicole Merten: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Davide Malfacini: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Asuka Inoue: Tohoku University
Philip Preis: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Katharina Simon: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Nelly Rüttiger: University Hospital Jena
Nicole Ziegler: University of Wuerzburg
Tobias Benkel: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Nina Katharina Schmitt: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Satoru Ishida: Tohoku University
Ines Müller: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Raphael Reher: University of Bonn
Kouki Kawakami: Tohoku University
Ayumi Inoue: Tohoku University
Ulrike Rick: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Toni Kühl: University of Bonn
Diana Imhof: University of Bonn
Junken Aoki: Tohoku University
Gabriele M. König: University of Bonn
Carsten Hoffmann: University Hospital Jena
Jesus Gomeza: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn
Jürgen Wess: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Evi Kostenis: Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02661-3

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