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GPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation

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  • J. Drube

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • R. S. Haider

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • E. S. F. Matthees

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • M. Reichel

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • J. Zeiner

    (University of Bonn)

  • S. Fritzwanker

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • C. Ziegler

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • S. Barz

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • L. Klement

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • J. Filor

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • V. Weitzel

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • A. Kliewer

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • E. Miess-Tanneberg

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • E. Kostenis

    (University of Bonn)

  • S. Schulz

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

  • C. Hoffmann

    (Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena)

Abstract

G protein-coupled receptors (GPCRs) activate G proteins and undergo a complex regulation by interaction with GPCR kinases (GRKs) and the formation of receptor–arrestin complexes. However, the impact of individual GRKs on arrestin binding is not clear. We report the creation of eleven combinatorial HEK293 knockout cell clones lacking GRK2/3/5/6, including single, double, triple and the quadruple GRK knockout. Analysis of β-arrestin1/2 interactions for twelve GPCRs in our GRK knockout cells enables the differentiation of two main receptor subsets: GRK2/3-regulated and GRK2/3/5/6-regulated receptors. Furthermore, we identify GPCRs that interact with β-arrestins via the overexpression of specific GRKs even in the absence of agonists. Finally, using GRK knockout cells, PKC inhibitors and β-arrestin mutants, we present evidence for differential receptor–β-arrestin1/2 complex configurations mediated by selective engagement of kinases. We anticipate our GRK knockout platform to facilitate the elucidation of previously unappreciated details of GRK-specific GPCR regulation and β-arrestin complex formation.

Suggested Citation

  • J. Drube & R. S. Haider & E. S. F. Matthees & M. Reichel & J. Zeiner & S. Fritzwanker & C. Ziegler & S. Barz & L. Klement & J. Filor & V. Weitzel & A. Kliewer & E. Miess-Tanneberg & E. Kostenis & S. S, 2022. "GPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28152-8
    DOI: 10.1038/s41467-022-28152-8
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    Cited by:

    1. Raphael S. Haider & Edda S. F. Matthees & Julia Drube & Mona Reichel & Ulrike Zabel & Asuka Inoue & Andy Chevigné & Cornelius Krasel & Xavier Deupi & Carsten Hoffmann, 2022. "β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Tobias Benkel & Mirjam Zimmermann & Julian Zeiner & Sergi Bravo & Nicole Merten & Victor Jun Yu Lim & Edda Sofie Fabienne Matthees & Julia Drube & Elke Miess-Tanneberg & Daniela Malan & Martyna Szpako, 2022. "How Carvedilol activates β2-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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