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α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands

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Abstract

The poor norepinephrine innervation and high density of Gi/o-coupled α2A- and α2C-adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D2-like receptor ligands, such as the D3 receptor agonist 7-OH-PIPAT and the D4 receptor agonist RO-105824, to α2-adrenoceptors in cortical and striatal tissue, which express α2A-adrenoceptors and both α2A- and α2C-adrenoceptors, respectively. The affinity of dopamine for α2-adrenoceptors was found to be similar to that for D1-like and D2-like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α2A- and α2C-adrenoceptors. Their ability to activate Gi/o proteins through α2A- and α2C-adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α2-adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α2A- and α2C-adrenoceptors was nearly identical to its binding to the crystallized D3 receptor. Therefore, we provide conclusive evidence that α2A- and α2C-adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D2-like receptor ligands, which calls for revisiting previous studies with those ligands.

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Acknowledgements

The authors would like to thank Dr. Céline Galés (INSERM) for generously sharing various Gi-like plasmid constructs for BRET experiments.

Funding

This research was supported by the “Ministerio de Economía y Competitividad” and European Regional Development Funds of the European Union Grant SAF2014-54840-R, the “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” Grant CB06/05/0064, the “Fundació La Marató de TV3” Grant 20140610, the fellowship from the Japan Society for the Promotion of Science, and intramural funds of the National Institute on Drug Abuse. Work in the Meiler Laboratory is supported through the NIH (R01 GM080403, R01 GM099842, R01 DK097376) and NSF (CHE 1305874).

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Author notes

  1. Marta Sánchez-Soto and Verònica Casadó-Anguera contributed equally to this work.

Authors and Affiliations

  1. Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Triad Technology Building, 333 Cassell Drive, Baltimore, MD, 21224, USA

    Marta Sánchez-Soto, Hideaki Yano, Ning-Sheng Cai & Sergi Ferré

  2. Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Diagonal 643, 08028, Barcelona, Spain

    Marta Sánchez-Soto, Verònica Casadó-Anguera, Estefanía Moreno, Enric I. Canela, Antoni Cortés & Vicent Casadó

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute of Biomedicine, University of Barcelona, Barcelona, Spain

    Marta Sánchez-Soto, Verònica Casadó-Anguera, Estefanía Moreno, Enric I. Canela, Antoni Cortés & Vicent Casadó

  4. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA

    Brian Joseph Bender & Jens Meiler

  5. Center for Structural Biology, Vanderbilt University, Nashville, TN, 37232, USA

    Brian Joseph Bender & Jens Meiler

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  1. Marta Sánchez-Soto
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Contributions

M. S.-S., V. C.-A., H. Y., N.-S. C., E. M., A. C., and B. J. B. performed the experiments and analyzed the data. H. Y., B. J. B., J. M., V. C., and S. F. designed the experiments. M. S.-S., V. C.-A., H. Y., B. J. B., J. M., E. I. C., V. C., and S. F. wrote the manuscript.

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Correspondence to Vicent Casadó or Sergi Ferré.

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Sánchez-Soto, M., Casadó-Anguera, V., Yano, H. et al. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands. Mol Neurobiol 55, 8438–8454 (2018). https://doi.org/10.1007/s12035-018-1004-1

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