The apparent cooperativity of some GPCRs does not necessarily imply dimerization.
When the binding of one ligand to its receptor is influenced by a second ligand acting on a different receptor, one might assume that the receptors dimerize, enabling allosteric interactions between ligands. This reasoning is frequently used to explain the complex binding curves of ligands of class A G-protein-coupled receptors (GPCRs). Here, we argue that in classical in vitro experiments the lack of GTP makes ligand-binding properties dependent on the available pool of G protein. Under such conditions a 1:1 GPCR-G-protein complex is stabilized, in which the G protein lacks a nucleotide and ligand binding is of high affinity. In vivo, this complex, a key intermediate of G-protein activation, never accumulates because of fast and irreversible GTP binding. In vitro, this complex creates interference in ligand binding when two monomeric GPCRs compete for the same G protein. Interestingly, this competition explains some in vivo effects of orphan GPCRs.
Chabre
Marc
M
Université de Nice Sophia-Antipolis, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France. chabre@ipmc.cnrs.fr
Deterre
Philippe
P
Antonny
Bruno
B
D001667:Binding, Competitive / Q000502:physiology; D002384:Catalysis; D019281:Dimerization; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*
D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins