Molecular basis of partial agonism at the neurotransmitter alpha2A-adrenergic receptor and Gi-protein heterotrimer.
To characterize the mechanism by which heterotrimeric G-proteins interpret the signals coming from various neurotransmitters of diverse efficacies (agonists and partial agonists) acting on alpha(2A)-adrenergic receptors, we used a fluorescent resonance energy transfer-based approach to study the effects of these partial agonists on the activation process of both the alpha(2A)-adrenergic receptor and its cognate G(i)-protein. We show that ligands of different efficacies switch the receptor into distinct conformational states, which in turn set the speed and extent of the G(i)-protein signaling. Thus, in cells the efficacy by which a receptor responds to diverse ligands is caused by the ability of the G-protein to differentiate between distinct receptor conformations. The data provide a new key characteristic underlying the mechanism of partial agonism at G-protein-coupled receptors.
Nikolaev
Viacheslav O
VO
Institute of Pharmacology and Toxicology, University of Würzburg, D-97078, Würzburg, Germany.
Hoffmann
Carsten
C
Bünemann
Moritz
M
Lohse
Martin J
MJ
Vilardaga
Jean-Pierre
JP
D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008024:Ligands; D051379:Mice; D011487:Protein Conformation; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C547768:ADRA2A protein, human; C547769:Adra2a protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D011993:Recombinant Fusion Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go