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 and Sergi Ferré ()
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Gemma Navarro: Department of Biochemistry and Physiology of the Faculty of Pharmacy of the University of Barcelona
Arnau Cordomí: Autonomous University of Barcelona
Verónica Casadó-Anguera: Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network
Estefanía Moreno: Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network
Ning-Sheng Cai: National Institutes of Health
Antoni Cortés: Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network
Enric I. Canela: Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network
Carmen W. Dessauer: University of Texas Health Science Center
Vicent Casadó: Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network
Leonardo Pardo: Autonomous University of Barcelona
Carme Lluís: Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and Institute of Biomedicine of the University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network
Sergi Ferré: National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03522-3

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