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Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain Navarro Brugal, Gemma Cordomí, Arnau Brugarolas Campillos, Marc Moreno Guillén, Estefanía Aguinaga Andrés, David Pérez-Benito, Laura Ferré, Sergi Cortés Tejedor, Antonio Casadó, Vicent Mallol Montero, Josefa Canela Campos, Enric I. (Enric Isidre), 1949- Lluís i Biset, Carme Pardo, Leonardo McCormick, Peter J. Franco Fernández, Rafael Adenosina Receptors cel·lulars Adenosine Cell receptors BACKGROUND: 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. 2018-03-12T12:29:24Z 2018-03-12T12:29:24Z 2018-02-28 2018-03-12T12:29:24Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1186/s12915-018-0491-x Bmc Biology, 2018, vol. 16, num. 1, p. 24 https://doi.org/10.1186/s12915-018-0491-x cc-by (c) Navarro Brugal, Gemma et al., 2018 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess BioMed Central Articles publicats en revistes (Bioquímica i Biomedicina Molecular)