Asymmetric conformational changes in a GPCR dimer controlled by G-proteins

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Abstract
G‐protein‐coupled receptors (GPCRs) are key players in cell communication. Although long considered as monomeric, it now appears that these heptahelical proteins can form homo‐ or heterodimers. Here, we analyzed the conformational changes in each subunit of a receptor dimer resulting from agonist binding to either one or both subunits by measuring the fluorescent properties of a leukotriene B4 receptor dimer with a single 5‐hydroxytryptophan‐labeled protomer. We show that a receptor dimer with only a single agonist‐occupied subunit can trigger G‐protein activation. We also show that the two subunits of the receptor dimer in the G‐protein‐coupled state differ in their conformation, even when both are liganded by the agonist. No such asymmetric conformational changes are observed in the absence of G‐protein, indicating that the interaction of the G‐protein with the receptor dimer brings specific constraints that prevent a symmetric functioning of this dimer. These data open new options for the differential signaling properties of GPCR dimers.