Selective Regulation of Gq Signaling by G Protein-Coupled Receptor Kinase 2: Direct Interaction of Kinase N Terminus with Activated Gαq
By M. Sallese, S. Mariggiò, Etrusca D'Urbano, L. Iacovelli, A. Blasi. Molecular Pharmacology, 2000
143 citations recorded by the source corpus.
In this study, we investigated the regulation of different G protein-coupled receptor (GPCR)-stimulated signaling pathways by GPCR kinase 2 (GRK2). We used thyrotropin receptor, which is coupled to different G proteins, to investigate the regulation of Gαs- and Gαq-mediated signaling (assessed by cAMP and inositol phosphate production, respectively). In transfected cells, both pathways were desensitized by GRK2. However a kinase-dead GRK2 mutant (GRK2-K220R) only decreased inositol phosphate production, indicating that GRK2 could regulate Gαq signaling through a phosphorylation-independent mechanism. Similar results were obtained with serotonin receptor 5-hydroxytryptamine 2C , which is coupled to Gαq. This effect was mimicked by the N-terminal domain of GRK2 (GRK2-Nter), but not by the C-terminal domain. In cells transfected with Gαq, direct activation of Gαq signaling (by AlF 4 − ) was desensitized by GRK2-Nter, indicating an effect at the Gα-level. For comparison, in parallel samples we studied a protein regulator of G protein signaling RGS4 and we found a similar regulatory profile. We therefore hypothesized that the GRK2-Nter could directly interact with the Gαq subunit to regulate its signaling, as demonstrated for several RGS proteins. This hypothesis is further supported by the presence, within the GRK2-Nter, of an RGS homology domain. In direct binding experiments, we found that GRK2-Nter interacts with Gαq (only when activated) but not with Gαs and Gαo. We conclude that GRK2, besides desensitizing the GPCR by phosphorylation, is able to selectively bind to Gαq and to regulate its signaling.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/91b0aba54ce52b91e0afc40d1b0c615154e65971
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In Cellular and Molecular Neuroscience
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Citations in the corpus
- Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling (2002, background): “This outcome most likely occurs by GRK2 sequestering G q or interfering with effector activation rather than through increased GTP hydrolysis (Carman et al., 1999; Sallese et al., 2000; Usui et al., 2000).”
- Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. (2001, unknown): “GRKs also contain amino-terminal RGS domains, suggesting that they may not only regulate GPCR signaling at the level of the receptor, but also regulate the activity of the G protein as well (Carman et al., 1999; Sallese et al., 2000).”