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  3. The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson's Disease

The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson's Disease

  • Mol Neurobiol. 2022 Oct;59(10):5955-5969. doi: 10.1007/s12035-022-02946-9.
Wilber Romero-Fernandez 1,  Jaume J Taura 2 3,  René A J Crans 2 3,  Marc Lopez-Cano 2 3,  Ramon Fores-Pons 4,  Manuel Narváez 5,  Jens Carlsson 1,  Francisco Ciruela 6 7,  Kjell Fuxe 8,  Dasiel O Borroto-Escuela 9 10
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala Univesity, 75124, Uppsala, Sweden.
  • 2 Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
  • 3 Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research, IDIBELL, L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
  • 4 Division of Cellular and Molecular Neurochemistry, Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851), Solnavägen 9, 17165, Stockholm, Sweden.
  • 5 Facultad de Medicina, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain.
  • 6 Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. fciruela@ub.edu.
  • 7 Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research, IDIBELL, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. fciruela@ub.edu.
  • 8 Division of Cellular and Molecular Neurochemistry, Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851), Solnavägen 9, 17165, Stockholm, Sweden. Kjell.Fuxe@ki.se.
  • 9 Division of Cellular and Molecular Neurochemistry, Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851), Solnavägen 9, 17165, Stockholm, Sweden. dasiel.borroto.escuela@ki.se.
  • 10 Laboratory of Receptomics and brain disorders, Department of Human Physiology, Faculty of Medicine, University of Malaga, Calle Jiménez Fraud, 10, 29071, Malaga, Malaga, Spain. dasiel.borroto.escuela@ki.se.
PMID: 35829830 DOI: 10.1007/s12035-022-02946-9
Abstract

The adenosine A2A receptor (A2AR), dopamine D2 receptor (D2R) and metabotropic glutamate receptor type 5 (mGluR5) form A2AR-D2R-mGluR5 heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the A2AR protomer plays a major role in the inhibitory modulation of the density and the allosteric receptor-receptor interaction within the D2R-mGluR5 heteromeric component of the A2AR-D2R-mGluR5 complex in vitro and in vivo. The A2AR and mGluR5 protomers interact and modulate D2R protomer recognition and signalling upon forming a trimeric complex from these receptors. Expression of A2AR in HEK293T cells co-expressing D2R and mGluR5 resulted in a significant and marked increase in the formation of the D2R-mGluR5 heteromeric component in both bioluminescence resonance energy transfer and proximity ligation assays. A highly significant increase of the the high-affinity component of D2R (D2RKi High) values was found upon cotreatment with the mGluR5 and A2AR agonists in the cells expressing A2AR, D2R and mGluR5 with a significant effect observed also with the mGluR5 agonist alone compared to cells expressing only D2R and mGluR5. In cells co-expressing A2AR, D2R and mGluR5, stimulation of the cells with an mGluR5 agonist like or D2R antagonist fully counteracted the D2R agonist-induced inhibition of the cAMP levels which was not true in cells only expressing mGluR5 and D2R. In agreement, the mGluR5-negative allosteric modulator raseglurant significantly reduced the haloperidol-induced catalepsy in mice, and in A2AR knockout mice, the haloperidol action had almost disappeared, supporting a functional role for mGluR5 and A2AR in enhancing D2R blockade resulting in catalepsy. The results represent a relevant example of integrative activity within higher-order heteroreceptor complexes.

Keywords

Adenosine A2A receptor; Allosteric modulation; Dopamine D2 receptor; Heteroreceptor complex; Metabotropic glutamate receptor 5; Receptor-receptor interaction.

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