Title |
Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain
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Published in |
BMC Biology, February 2018
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DOI | 10.1186/s12915-018-0491-x |
Pubmed ID | |
Authors |
Gemma Navarro, Arnau Cordomí, Marc Brugarolas, Estefanía Moreno, David Aguinaga, Laura Pérez-Benito, Sergi Ferre, Antoni Cortés, Vicent Casadó, Josefa Mallol, Enric I. Canela, Carme Lluís, Leonardo Pardo, Peter J. McCormick, Rafael Franco |
Abstract |
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. 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 Giand Gsproteins. We identified a new mechanism of signal transduction that implies a cross-communication between Giand Gsproteins 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. |
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Mendeley readers
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Researcher | 11 | 13% |
Student > Master | 10 | 12% |
Student > Bachelor | 8 | 9% |
Professor > Associate Professor | 7 | 8% |
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Unknown | 19 | 22% |
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Other | 13 | 15% |
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