Navarro Brugal, GemmaCordomí, ArnauBrugarolas Campillos, MarcMoreno Guillén, EstefaníaAguinaga Andrés, DavidPérez-Benito, LauraFerré, SergiCortés Tejedor, AntonioCasadó, VicentMallol Montero, JosefaCanela Campos, Enric I. (Enric Isidre), 1949-Lluís i Biset, CarmePardo, LeonardoMcCormick, Peter J.Franco Fernández, Rafael2018-03-122018-03-122018-02-281741-7007https://hdl.handle.net/2445/120611BACKGROUND: G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A1R or A2AR) can form A1R-A2AR heteromers (A1-A2AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for A1R and A2AR, allowing the heteromeric receptor to detect its concentration by integrating the downstream Gi- and Gs-dependent signals. cAMP accumulation and β-arrestin recruitment assays have shown that, within the complex, activation of A2AR impedes signaling via A1R. RESULTS: We examined the mechanism by which A1-A2AHet integrates Gi- and Gs-dependent signals. A1R blockade by A2AR in the A1-A2AHet is not observed in the absence of A2AR activation by agonists, in the absence of the C-terminal domain of A2AR, or in the presence of synthetic peptides that disrupt the heteromer interface of A1-A2AHet, indicating that signaling mediated by A1R and A2AR is controlled by both Gi and Gs proteins. CONCLUSIONS: We identified a new mechanism of signal transduction that implies a cross-communication between Gi and Gs proteins guided by the C-terminal tail of the A2AR. This mechanism provides the molecular basis for the operation of the A1-A2AHet as an adenosine concentration-sensing device that modulates the signals originating at both A1R and A2AR.15 p.application/pdfengcc-by (c) Navarro Brugal, Gemma et al., 2018http://creativecommons.org/licenses/by/3.0/esAdenosinaReceptors cel·lularsAdenosineCell receptorsinfo:eu-repo/semantics/article6776082018-03-12info:eu-repo/semantics/openAccess29486745