A new D₂ dopamine receptor agonist allosterically modulates A(2A) adenosine receptor signalling by interacting with the A(2A)/D₂ receptor heteromer.
The structural and functional interaction between D₂ dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D₂DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D₂DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D₂DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D₂DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D₂DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D₂ dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D₂DR and modulator of A(2A)-D₂ receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D₂R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D₂DR homomers and heteromers and induced A(2A)AR/D₂DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D₂ DR heteromers.
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Maria Letizia
ML
Trincavelli
Simona
S
Daniele
Elisabetta
E
Orlandini
Gemma
G
Navarro
Vicent
V
Casadó
Chiara
C
Giacomelli
Susanna
S
Nencetti
Elisa
E
Nuti
Marco
M
Macchia
Harald
H
Huebner
Peter
P
Gmeiner
Armando
A
Rossello
Carmen
C
Lluís
Claudia
C
Martini
D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007700:Kinetics; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D020239:Receptor Cross-Talk / Q000502:physiology; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine
C572945:3-(3,4-dimethylphenyl)-1-(2-piperidin-1-ylethyl)piperidine; D018491:Dopamine Agonists; D010880:Piperidines; D043683:Receptors, Adenosine A2; D017448:Receptors, Dopamine D2