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A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors

Author

Listed:
  • Julian Brands

    (University of Bonn
    University of Bonn)

  • Sergi Bravo

    (University of Bonn)

  • Lars Jürgenliemke

    (University of Bonn
    University of Bonn)

  • Lukas Grätz

    (Karolinska Institutet)

  • Hannes Schihada

    (Philipps-University Marburg)

  • Fabian Frechen

    (University of Bonn)

  • Judith Alenfelder

    (University of Bonn)

  • Cy Pfeil

    (University of Bonn
    University of Bonn
    Vrije Universiteit Amsterdam)

  • Paul Georg Ohse

    (University of Bonn)

  • Suzune Hiratsuka

    (Tohoku University)

  • Kouki Kawakami

    (Tohoku University
    The University of Tokyo)

  • Luna C. Schmacke

    (Philipps-University Marburg)

  • Nina Heycke

    (University of Bonn)

  • Asuka Inoue

    (Tohoku University
    Kyoto University)

  • Gabriele König

    (University of Bonn)

  • Alexander Pfeifer

    (University of Bonn)

  • Dagmar Wachten

    (University of Bonn)

  • Gunnar Schulte

    (Karolinska Institutet)

  • Torsten Steinmetzer

    (Philipps-University Marburg)

  • Val J. Watts

    (Purdue University)

  • Jesús Gomeza

    (University of Bonn)

  • Katharina Simon

    (University of Bonn
    University of Padova)

  • Evi Kostenis

    (University of Bonn)

Abstract

A long-held tenet in inositol-lipid signaling is that cleavage of membrane phosphoinositides by phospholipase Cβ (PLCβ) isozymes to increase cytosolic Ca2+ in living cells is exclusive to Gq- and Gi-sensitive G protein-coupled receptors (GPCRs). Here we extend this central tenet and show that Gs-GPCRs also partake in inositol-lipid signaling and thereby increase cytosolic Ca2+. By combining CRISPR/Cas9 genome editing to delete Gαs, the adenylyl cyclase isoforms 3 and 6, or the PLCβ1-4 isozymes, with pharmacological and genetic inhibition of Gq and G11, we pin down Gs-derived Gβγ as driver of a PLCβ2/3-mediated cytosolic Ca2+ release module. This module does not require but crosstalks with Gαs-dependent cAMP, demands Gαq to release PLCβ3 autoinhibition, but becomes Gq-independent with mutational disruption of the PLCβ3 autoinhibited state. Our findings uncover the key steps of a previously unappreciated mechanism utilized by mammalian cells to finetune their calcium signaling regulation through Gs-GPCRs.

Suggested Citation

  • Julian Brands & Sergi Bravo & Lars Jürgenliemke & Lukas Grätz & Hannes Schihada & Fabian Frechen & Judith Alenfelder & Cy Pfeil & Paul Georg Ohse & Suzune Hiratsuka & Kouki Kawakami & Luna C. Schmacke, 2024. "A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51991-6
    DOI: 10.1038/s41467-024-51991-6
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