A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors
A long-held tenet in inositol-lipid signaling is that cleavage of membrane phosphoinositides by phospholipase Cβ (PLCβ) isozymes to increase cytosolic Ca<sup>2+</sup> 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 Ca<sup>2+</sup>. By combining CRISPR/Cas9 genome editing to delete Gα<sub>s</sub>, 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 Ca<sup>2+</sup> release module. This module does not require but crosstalks with Gα<sub>s</sub>-dependent cAMP, demands Gα<sub>q</sub> 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.
Authors
- Hannes Schihada (ORCID: https://orcid.org/0000-0002-1889-1636)
- Katharina Simon
- Luna C. Schmacke (ORCID: https://orcid.org/0000-0003-1229-4248)
- Judith Alenfelder (ORCID: https://orcid.org/0009-0009-3733-3443)
- Julian Brands
- Nina Heycke
- Evi Kostenis (ORCID: https://orcid.org/0000-0001-8284-5514)
- Gunnar Schulte (ORCID: https://orcid.org/0000-0002-2700-7013)
- Gabriele M. König (ORCID: https://orcid.org/0000-0003-0003-4916)
- Asuka Inoue (ORCID: https://orcid.org/0000-0003-0805-4049)
- Val J. Watts (ORCID: https://orcid.org/0000-0003-1581-2936)
- Lukas Grätz (ORCID: https://orcid.org/0000-0001-6755-0742)
- Torsten Steinmetzer (ORCID: https://orcid.org/0000-0001-6523-4754)
- Fabian Frechen (ORCID: https://orcid.org/0009-0003-1279-2842)
- Alexander Pfeifer (ORCID: https://orcid.org/0000-0001-8805-6831)
- Dagmar Wachten (ORCID: https://orcid.org/0000-0003-4800-6332)
- Kouki Kawakami (ORCID: https://orcid.org/0000-0002-2507-8619)
- Sergi Bravo (ORCID: https://orcid.org/0000-0001-5541-2860)
- Suzune Hiratsuka
- Jesús Gomeza (ORCID: https://orcid.org/0000-0002-2452-8016)
- Lars Jürgenliemke (ORCID: https://orcid.org/0009-0001-2701-9276)
- Cy Pfeil
- Paul Georg Ohse
Institutions
- University of Bonn (DE)
- University of Padua (IT)
- Philipps University of Marburg (DE)
- Tohoku University (JP)
- Purdue University West Lafayette (US)
- Kyoto University (JP)
- Kyoto Pharmaceutical University (JP)
- University Hospital Bonn (DE)
- Karolinska Institutet (SE)
- The University of Tokyo (JP)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1038/s41467-024-51991-6
- Citations
- 21
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.91
Funders
- Japan Agency for Medical Research and Development
- Deutsche Forschungsgemeinschaft
- Vetenskapsrådet
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency