| Autor: |
Brands, Julian, Bravo, Sergi, Jürgenliemke, Lars, Grätz, Lukas, Schihada, Hannes, Frechen, Fabian, Alenfelder, Judith, Pfeil, Cy, Ohse, Paul Georg, Hiratsuka, Suzune, Kawakami, Kouki, Schmacke, Luna C., Heycke, Nina, Inoue, Asuka, König, Gabriele, Pfeifer, Alexander, Wachten, Dagmar, Schulte, Gunnar, Steinmetzer, Torsten, Watts, Val J. |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/3/2024, Vol. 15 Issue 1, p1-21, 21p |
| Abstrakt: |
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. Gs heterotrimers are considered to be poor providers of free Gβγ subunits. Here, the authors show that—despite this—Gs-derived Gβγ dimers are active transducers of GPCR-initiated Ca2+ signals involving phosphoinositide-based signaling routes. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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