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Heteroreceptor Complexes Implicated in Parkinson’s Disease

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G-Protein-Coupled Receptor Dimers

Part of the book series: The Receptors ((REC,volume 33))

Abstract

Heteromerization alters GPCR recognition, G-protein activation, receptor signaling and trafficking, thus changing receptor protomer pharmacology and function. This review deals mainly with the A2AR-D2R and A1R-D1R heteroreceptor complexes, their balance with dopamine and adenosine isoreceptor complexes and their role in Parkinson’s disease and its treatment. The major technique used for the visualization of the heteroreceptor complexes in the brain was the proximity ligation assay. A1R-D1R and putative A1R-D1R-D3R heteroreceptor complexes appear to exist in the direct pathway. Upon agonist activation the A1R protomer exerts a brake on the D1R protomer signaling of these complexes reducing the activity of the direct pathway with reduction of movement initiation. D1R-NMDAR and D1R-H3R-NMDAR heteroreceptor complexes in the striatal glutamate synapses integrate synaptic and volume transmission, where in the former complexes the D1R protomer enhances NMDAR signaling with enhancement of movements. A2AR-D2R and A2AR-D2R-mGlu5R heteroreceptor complexes with antagonistic receptor-receptor interactions exist in the dorsal striato-pallidal GABA neurons mediating motor inhibition. The A2AR and mGlu5R antagonists synergize to increase D2R protomer signaling by removing the A2AR and mGlu5R brakes on the D2R protomer signaling and heterobivalent compounds built of A2AR and mGlu5R antagonists may specifically and substantially remove these brakes reducing motor inhibition with development of antiparkinson actions.

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Acknowledgements

The work was supported by grants from the Swedish Medical Research Council (62X-00715-50-3) and Parkinsonfonden to KF, by AFA Försäkring (130328) to KF and DOBE, and by the Hjärnfonden to DOBE. DOB-E belongs to Academia de Biólogos Cubanos.

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Authors and Affiliations

  1. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Dasiel O. Borroto-Escuela Ph.D., MBA & Kjell Fuxe M.D., Ph.D.

  2. Department of Earth, Life and Environmental Sciences, Section of Physiology, Campus Scientifico Enrico Mattei, University of Urbino, Urbino, Italy

    Dasiel O. Borroto-Escuela Ph.D., MBA

  3. Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Yaguajay, Cuba

    Dasiel O. Borroto-Escuela Ph.D., MBA

  4. Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Universidad de Málaga, Málaga, Spain

    Manuel Narváez

  5. Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Gemma Navarro & Rafael Franco

  6. Centro de Investigación en Red. Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Gemma Navarro & Rafael Franco

Authors
  1. Dasiel O. Borroto-Escuela Ph.D., MBA
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  2. Manuel Narváez
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  3. Gemma Navarro
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  4. Rafael Franco
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  5. Kjell Fuxe M.D., Ph.D.
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Corresponding author

Correspondence to Kjell Fuxe M.D., Ph.D. .

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Editors and Affiliations

  1. Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA

    Katharine Herrick-Davis

  2. Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom

    Graeme Milligan

  3. Department of Physiology and Biochemistry, University of Malta, Msida, Malta

    Giuseppe Di Giovanni

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Borroto-Escuela, D.O., Narváez, M., Navarro, G., Franco, R., Fuxe, K. (2017). Heteroreceptor Complexes Implicated in Parkinson’s Disease. In: Herrick-Davis, K., Milligan, G., Di Giovanni, G. (eds) G-Protein-Coupled Receptor Dimers. The Receptors, vol 33. Humana Press, Cham. https://doi.org/10.1007/978-3-319-60174-8_20

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