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Trends Pharmacol Sci. 2009 Apr;30(4):182-7. doi: 10.1016/j.tips.2009.01.003. Epub 2009 Mar 5.

The apparent cooperativity of some GPCRs does not necessarily imply dimerization.

Author information

1
Université de Nice Sophia-Antipolis, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France. chabre@ipmc.cnrs.fr

Abstract

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.

PMID:
19269046
DOI:
10.1016/j.tips.2009.01.003
[Indexed for MEDLINE]

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