Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase

Gemma Navarro, Arnau Cordomí, Verónica Casadó-Anguera, Estefanía Moreno, Ning Sheng Cai, Antoni Cortés, Enric I. Canela, Carmen W. Dessauer, Vicent Casadó, Leonardo Pardo, Carme Lluís, Sergi Ferré

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Abstract

© 2018 The Author(s). G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of heteromers of adenosine A2A receptor and dopamine D2 receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR.
Original languageEnglish
Article number1242
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 1 Dec 2018

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