The apparent cooperativity of some GPCRs does not necessarily imply dimerization

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 30; no. 4; pp. 182 - 187
• Main Authors: Chabre, Marc, Deterre, Philippe, Antonny, Bruno
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2009; Elsevier
• Subjects: Advanced Basic Science; Binding, Competitive; Binding, Competitive - physiology; Biochemistry, Molecular Biology; Catalysis; Dimerization; GTP-Binding Proteins; GTP-Binding Proteins - metabolism; Humans; Kinetics; Life Sciences; Receptors, G-Protein-Coupled; Receptors, G-Protein-Coupled - physiology
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2009.01.003

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.