Useful pharmacological parameters for G-protein-coupled receptor homodimers obtained from competition experiments. Agonist-antagonist binding modulation.
Many G-protein-coupled receptors (GPCRs) are expressed on the plasma membrane as dimers. Since drug binding data are currently fitted using equations developed for monomeric receptors, the interpretation of the pharmacological data are equivocal in many cases. As reported here, GPCR dimer models account for changes in competition curve shape as a function of the radioligand concentration used, something that cannot be explained by monomeric receptor models. Macroscopic equilibrium dissociation constants for the agonist and homotropic cooperativity index reflecting the intramolecular communication within the dopamine D1 or adenosine A2A receptor homodimer as well as hybrid equilibrium dissociation constant, which reflects the antagonist/agonist modulation may be calculated by fitting binding data from antagonist/agonist competition experiments to equations developed from dimer receptor models. Comparing fitting the data by assuming a classical monomeric receptor model or a dimer model, it is shown that dimer receptor models provide more clues useful in drug discovery than monomer-based models.
Casadó
Vicent
V
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Avda. Diagonal 465, 08028 Barcelona, Spain. vcasado@ub.edu
Ferrada
Carla
C
Bonaventura
Jordi
J
Gracia
Eduard
E
Mallol
Josefa
J
Canela
Enric I
EI
Lluís
Carmen
C
Cortés
Antoni
A
Franco
Rafael
R
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods; D008954:Models, Biological; D010627:Phenethylamines / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012756:Sheep
D001552:Benzazepines; D018491:Dopamine Agonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D043562:Receptors, G-Protein-Coupled; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C067113:SK&F 81297; D000241:Adenosine