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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.00829

Mapping the interface of a GPCR dimer: A structural model of the A2A adenosine and D2 dopamine receptor heteromer

 Dasiel O. Borroto-Escuela1, David Rodríguez2, Wilber Romero-Fernandez3, Jon Kapla3, Mariama Jaiteh3, Anirudh Ranganathan2, Tvezana Lazarova4,  Kjell Fuxe1 and  Jens Carlsson3*
  • 1Department of Neuroscience, Karolinska Institute (KI), Sweden
  • 2Department of Biochemistry and Biophysics, Science for Life Laboratory (SciLifeLab), Sweden
  • 3Department of Cell and Molecular Biology, Uppsala University, Sweden
  • 4Department of Biochemistry and Molecular Biology, Institute of Neuroscience, Faculty of Medicine, Autonomous University of Barcelona, Spain

The A2A adenosine (A2AR) and D2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A2AR-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding the molecular determinants of A2AR-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A2AR-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modelled based on the effects of peptides derived from the 14 transmembrane (TM) helices on A2AR-D2R receptor-receptor interactions in bioluminescence resonance energy transfer and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A2AR blocked heterodimer interactions and disrupted the allosteric effect of A2AR activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A2AR-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A2AR-D2R interactions in bioluminescence resonance energy transfer experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A2AR-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

Keywords: G protein-coupled receptor, dimerization, D2 dopamine receptor, A2A adenosine receptor, heteroreceptor complexes, Dimer interface, allosteric modulation

Received: 08 Feb 2018; Accepted: 10 Jul 2018.

Edited by:

Dominique Massotte, UPR3212 Institut des Neurosciences Cellulaires et Intégratives (INCI), France

Reviewed by:

Peter Vanhoutte, Centre national de la recherche scientifique (CNRS), France
Francesca Fanelli, Università degli Studi di Modena e Reggio Emilia, Italy
Juan Fernandez-Recio, Barcelona Supercomputing Center, Spain
Ahmed Hasbi, University of Toronto, Canada  

Copyright: © 2018 Borroto-Escuela, Rodríguez, Romero-Fernandez, Kapla, Jaiteh, Ranganathan, Lazarova, Fuxe and Carlsson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Jens Carlsson, Uppsala University, Department of Cell and Molecular Biology, Uppsala, 751 24, Uppsala, Sweden, jens.carlsson@icm.uu.se