RT Journal Article
T1 The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson’s Disease
A1 Romero-Fernandez, Wilber
A1 Taura, Jaume J.
A1 Crans, René A. J.
A1 Lopez-Cano, Marc
A1 Fores-Pons, Ramon
A1 Narváez, Manuel
A1 Carlsson, Jens
A1 Ciruela, Francisco
A1 Fuxe, Kjell
A1 Borroto-Escuela, Dasiel O.
K1 Parkinson, Enfermedad de
K1 Dopamina - Receptores
AB 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.
PB Springer
SN 0893-7648
YR 2022
FD 2022-07-12
LK https://hdl.handle.net/10630/45021
UL https://hdl.handle.net/10630/45021
LA eng
NO Romero-Fernandez, W., Taura, J.J., Crans, R.A.J. et al. 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 59, 5955–5969 (2022). https://doi.org/10.1007/s12035-022-02946-9
NO Karolinska Institutet (Open access funding)
NO Swedish Research Council (Vetenskapsrådet)
NO ParkinsonFonden
NO Hjärnfonden
NO Karolinska Institutet Forskningsstiftelser
NO Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI) – EMERGIA (Junta de Andalucía)
NO Olle Engkvists Stiftelse
NO MCIN/AEI (Ministerio de Ciencia e Innovación / Agencia Estatal de Investigación, España)
NO FEDER (Fondo Europeo de Desarrollo Regional)
NO CERCA Programme (Generalitat de Catalunya) / IDIBELL (institutional support)
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 13 abr 2026