An inactive receptor-G protein complex maintains the dynamic range of agonist-induced signaling

Significance G protein-coupled receptors (GPCRs) are targeted by a large fraction of approved drugs and regulate many important cellular processes. Conventional signaling by GPCRs is triggered when agonist-activated receptors associate with heterotrimeric G proteins. We found that serotonin 5-HT 7 receptors couple to G s proteins in an unconventional manner, in which agonist binding instead promotes dissociation of preexisting inactive 5-HT 7 –G s complexes. Therefore, agonists can initiate signaling via two distinct mechanisms, by promoting the association of active receptors and G proteins and by promoting dissociation of inactive receptors and G proteins.