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

• Published in: Nature communications 2018-03, Vol.9 (1), p.1242-12, Article 1242
• Main Authors: Navarro, Gemma, Cordomí, Arnau, Casadó-Anguera, Verónica, Moreno, Estefanía, Cai, Ning-Sheng, Cortés, Antoni, Canela, Enric I., Dessauer, Carmen W., Casadó, Vicent, Pardo, Leonardo, Lluís, Carme, Ferré, Sergi
• Format: Article
• Language: English
• Subjects: 13; 631/378/340; 631/45/612/194; 631/80/86; 96/1; 96/106; 96/109; 96/35; 96/95; Adenosina; Adenosine; Adenylyl Cyclases - metabolism; Animals; Bacterial Proteins - metabolism; Biochemistry; Cell receptors; Computer Simulation; Cyclic AMP - metabolism; Dopamine; Dopamine D2 receptors; G protein-coupled receptors; GTP-Binding Proteins - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Interfaces; Ligands; Luminescent Proteins - metabolism; Macromolecular Substances; Macromolecules; multidisciplinary; Neurons - metabolism; Neurosciences; Peptides; Peptides - chemistry; Physiology; Protein Binding; Protein Multimerization; Protein Structure, Quaternary; Proteins; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A - metabolism; Receptors; Receptors cel·lulars; Receptors, Dopamine D2 - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03522-3

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 A 2A receptor and dopamine D 2 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. It is unclear whether GPCRs, G proteins and adenylyl cyclase (AC) associate through random collisions or defined pre-coupling mechanisms. Using a peptide-based approach, the authors show that heteromers of adenosine A 2A and dopamine D 2 receptors form pre-coupled complexes with their cognate G proteins and AC5.