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Molecular Neurobiology

, Volume 56, Issue 10, pp 6756–6769 | Cite as

Biased G Protein-Independent Signaling of Dopamine D1-D3 Receptor Heteromers in the Nucleus Accumbens

  • Xavier Guitart
  • Estefanía Moreno
  • William Rea
  • Marta Sánchez-Soto
  • Ning-Sheng Cai
  • César Quiroz
  • Vivek Kumar
  • Liam Bourque
  • Antoni Cortés
  • Enric I. Canela
  • Christopher Bishop
  • Amy H. Newman
  • Vicent CasadóEmail author
  • Sergi FerréEmail author
Article

Abstract

Several studies found in vitro evidence for heteromerization of dopamine D1 receptors (D1R) and D3 receptors (D3R), and it has been postulated that functional D1R-D3R heteromers that are normally present in the ventral striatum mediate synergistic locomotor-activating effects of D1R and D3R agonists in rodents. Based also on results obtained in vitro, with mammalian transfected cells, it has been hypothesized that those behavioral effects depend on a D1R-D3R heteromer-mediated G protein-independent signaling. Here, we demonstrate the presence on D1R-D3R heteromers in the mouse ventral striatum by using a synthetic peptide that selectively destabilizes D1R-D3R heteromers. Parallel locomotor activity and ex vivo experiments in reserpinized mice and in vitro experiments in D1R-D3R mammalian transfected cells were performed to dissect the signaling mechanisms of D1R-D3R heteromers. Co-administration of D1R and D3R agonists in reserpinized mice produced synergistic locomotor activation and a selective synergistic AKT phosphorylation in the most ventromedial region of the striatum in the shell of the nucleus accumbens. Application of the destabilizing peptide in transfected cells and in the shell of the nucleus accumbens allowed demonstrating that both in vitro and in vivo co-activation of D3R induces a switch from G protein-dependent to G protein-independent D1R-mediated signaling determined by D1R-D3R heteromerization. The results therefore demonstrate that a biased G protein-independent signaling of D1R-D3R heteromers localized in the shell of the nucleus accumbens mediate the locomotor synergistic effects of D1R and D3R agonists in reserpinized mice.

Keywords

GPCR heteromers Dopamine D1 receptor Dopamine D3 receptor Reserpine Functional selectivity 

Notes

Funding Information

This work is supported by the intramural funds of the National Institute on Drug Abuse, “Ministerio de Economía y Competitividad” and European Regional Development Funds of the European Union (Grants SAF2014-54840-R and SAF2017-87629-R), “Fundació La Marató de TV3” (Grant 20140610), and “Generalitat de Catalunya” (Grant 2017-SGR-1497).

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Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  • Xavier Guitart
    • 1
  • Estefanía Moreno
    • 2
  • William Rea
    • 1
  • Marta Sánchez-Soto
    • 1
  • Ning-Sheng Cai
    • 1
  • César Quiroz
    • 1
  • Vivek Kumar
    • 3
  • Liam Bourque
    • 1
  • Antoni Cortés
    • 2
  • Enric I. Canela
    • 2
  • Christopher Bishop
    • 4
  • Amy H. Newman
    • 3
  • Vicent Casadó
    • 2
    Email author
  • Sergi Ferré
    • 1
    Email author
  1. 1.Integrative Neurobiology SectionNational Institute on Drug Abuse, Intramural Research Program, National Institutes of HealthBaltimoreUSA
  2. 2.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 NetworkBarcelonaSpain
  3. 3.Medicinal Chemistry SectionNational Institute on Drug Abuse, Intramural Research Program, National Institutes of HealthBaltimoreUSA
  4. 4.Behavioral Neuroscience Program, Department of PsychologyBinghamton UniversityBinghamtonUSA

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