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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Pfeil, EM; Brands, J; Merten, N; Vögtle, T; Vescovo, M; Rick, U; Albrecht, IM; Heycke, N; Kawakami, K; Ono, Y; Ngako Kadji, FM; Hiratsuka, S; Aoki, J; Häberlein, F; Matthey, M; Garg, J; Hennen, S; Jobin, ML; Seier, K; Calebiro, D; Pfeifer, A; Heinemann, A; Wenzel, D; König, GM; Nieswandt, B; Fleischmann, BK; Inoue, A; Simon, K; Kostenis, E.
Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs.
Mol Cell. 2020; 80(6):940-954 Doi: 10.1016/j.molcel.2020.10.027
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Co-Autor*innen der Med Uni Graz

Heinemann Akos

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Abstract:

Mechanisms that control mobilization of cytosolic calcium [Ca²⁺]_i are key for regulation of numerous eukaryotic cell functions. One such paradigmatic mechanism involves activation of phospholipase Cβ (PLCβ) enzymes by G protein βγ subunits from activated Gα_i-Gβγ heterotrimers. Here, we report identification of a master switch to enable this control for PLCβ enzymes in living cells. We find that the Gα_i-Gβγ-PLCβ-Ca²⁺ signaling module is entirely dependent on the presence of active Gα_q. If Gα_q is pharmacologically inhibited or genetically ablated, Gβγ can bind to PLCβ but does not elicit Ca²⁺ signals. Removal of an auto-inhibitory linker that occludes the active site of the enzyme is required and sufficient to empower "stand-alone control" of PLCβ by Gβγ. This dependence of Gi-Gβγ-Ca²⁺ on Gα_q places an entire signaling branch of G-protein-coupled receptors (GPCRs) under hierarchical control of Gq and changes our understanding of how Gi-GPCRs trigger [Ca²⁺]_i via PLCβ enzymes. Copyright © 2020 Elsevier Inc. All rights reserved.

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