Cross-communication between G and G in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain
G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (AR or AR) can form AR-AR heteromers (A-AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediat...
| Autores: | , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:253457 |
| Acceso en línea: | https://ddd.uab.cat/record/253457 https://dx.doi.org/urn:doi:10.1186/s12915-018-0491-x |
| Access Level: | acceso abierto |
| Palabra clave: | C-terminal domain GPCR Heterotetramer BRET Molecular modeling |
| Sumario: | G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (AR or AR) can form AR-AR heteromers (A-AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for AR and AR, allowing the heteromeric receptor to detect its concentration by integrating the downstream G- and G-dependent signals. cAMP accumulation and β-arrestin recruitment assays have shown that, within the complex, activation of AR impedes signaling via AR. We examined the mechanism by which A-AHet integrates G- and G-dependent signals. AR blockade by AR in the A-AHet is not observed in the absence of AR activation by agonists, in the absence of the C-terminal domain of AR, or in the presence of synthetic peptides that disrupt the heteromer interface of A-AHet, indicating that signaling mediated by AR and AR is controlled by both G and G proteins. We identified a new mechanism of signal transduction that implies a cross-communication between G and G proteins guided by the C-terminal tail of the AR. This mechanism provides the molecular basis for the operation of the A-AHet as an adenosine concentration-sensing device that modulates the signals originating at both AR and AR. |
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