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

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, Nina Heycke, Asuka Inoue, Gabriele König, Alexander Pfeifer, Dagmar Wachten, Gunnar Schulte, Torsten Steinmetzer, Val J. Watts, Jesús Gomeza, Katharina Simon and Evi Kostenis ()
Additional contact information
Julian Brands: University of Bonn
Sergi Bravo: University of Bonn
Lars Jürgenliemke: 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
Paul Georg Ohse: University of Bonn
Suzune Hiratsuka: Tohoku University
Kouki Kawakami: Tohoku University
Luna C. Schmacke: Philipps-University Marburg
Nina Heycke: University of Bonn
Asuka Inoue: Tohoku 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
Evi Kostenis: University of Bonn

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51991-6

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DOI: 10.1038/s41467-024-51991-6

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