Agonist-induced formation of unproductive receptor-G 12 complexes
| Autor: | Kouki Kawakami, Jonathan A. Javitch, Michel Bouvier, Sumin Lu, Najeah Okashah, Joris Zhou, Signe Mathiasen, Nevin A. Lambert, Asuka Inoue, Shane C. Wright |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
0303 health sciences Multidisciplinary Kinase Chemistry G protein medicine.drug_class viruses fungi Cell biology 03 medical and health sciences 0302 clinical medicine Arrestin medicine Smoothened Receptor Ternary complex 030217 neurology & neurosurgery 030304 developmental biology G protein-coupled receptor |
| Zdroj: | Proceedings of the National Academy of Sciences. 117:21723-21730 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2003787117 |
| Popis: | G proteins are activated when they associate with G protein-coupled receptors (GPCRs), often in response to agonist-mediated receptor activation. It is generally thought that agonist-induced receptor-G protein association necessarily promotes G protein activation and, conversely, that activated GPCRs do not interact with G proteins that they do not activate. Here we show that GPCRs can form agonist-dependent complexes with G proteins that they do not activate. Using cell-based bioluminescence resonance energy transfer (BRET) and luminescence assays we find that vasopressin V2 receptors (V2R) associate with both Gs and G12 heterotrimers when stimulated with the agonist arginine vasopressin (AVP). However, unlike V2R-Gs complexes, V2R-G12 complexes are not destabilized by guanine nucleotides and do not promote G12 activation. Activating V2R does not lead to signaling responses downstream of G12 activation, but instead inhibits basal G12-mediated signaling, presumably by sequestering G12 heterotrimers. Overexpressing G12 inhibits G protein receptor kinase (GRK) and arrestin recruitment to V2R and receptor internalization. Formyl peptide (FPR1 and FPR2) and Smoothened (Smo) receptors also form complexes with G12 that are insensitive to nucleotides, suggesting that unproductive GPCR-G12 complexes are not unique to V2R. These results indicate that agonist-dependent receptor-G protein association does not always lead to G protein activation and may in fact inhibit G protein activation. |
| Databáze: | OpenAIRE |
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