Cross-communication between G <inf>i</inf> and G <inf>s</inf> in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain

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

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24 Citations (Scopus)

Abstract

© 2018 Franco et al. Background: G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A 1 R or A 2A R) can form A 1 R-A 2A R heteromers (A 1 -A 2A Het), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for A 1 R and A 2A R, allowing the heteromeric receptor to detect its concentration by integrating the downstream G i - and G s -dependent signals. cAMP accumulation and β-arrestin recruitment assays have shown that, within the complex, activation of A 2A R impedes signaling via A 1 R. Results: We examined the mechanism by which A 1 -A 2A Het integrates G i - and G s -dependent signals. A 1 R blockade by A 2A R in the A 1 -A 2A Het is not observed in the absence of A 2A R activation by agonists, in the absence of the C-terminal domain of A 2A R, or in the presence of synthetic peptides that disrupt the heteromer interface of A 1 -A 2A Het, indicating that signaling mediated by A 1 R and A 2A R is controlled by both G i and G s proteins. Conclusions: We identified a new mechanism of signal transduction that implies a cross-communication between G i and G s proteins guided by the C-terminal tail of the A 2A R. This mechanism provides the molecular basis for the operation of the A 1 -A 2A Het as an adenosine concentration-sensing device that modulates the signals originating at both A 1 R and A 2A R.
Original languageEnglish
Article number24
JournalBMC Biology
Volume16
Issue number1
DOIs
Publication statusPublished - 28 Feb 2018

Keywords

  • BRET
  • C-terminal domain
  • GPCR
  • Heterotetramer
  • Molecular modeling

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    Navarro, G., Cordomí, A., Brugarolas, M., Moreno, E., Aguinaga, D., Pérez-Benito, L., Ferre, S., Cortés, A., Casadó, V., Mallol, J., Canela, E. I., Lluís, C., Pardo, L., McCormick, P. J., & Franco, R. (2018). Cross-communication between G <inf>i</inf> and G <inf>s</inf> in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain. BMC Biology, 16(1), [24]. https://doi.org/10.1186/s12915-018-0491-x