Deciphering the specific role of G_αi/o isoforms: functional selective oxytocin ligands and somatostatin SST5 receptor mutants

Receptor coupling to different G-proteins and β-arrestins has been described for a number of GPCRs (G-protein-coupled receptors), suggesting a multi-state model of receptor activation in which each receptor can assume a number of different active conformations, each capable of promoting the coupling to a specific effector. Consistently, functional-selective ligands and biased agonists have been described to be able to induce and/or stabilize only a subset of specific active conformations. Furthermore, GPCR mutants deficient in selective coupling have been reported. Functional selective ligands and receptor mutants thus constitute unique tools to dissect the specific roles of different effectors, in particular among the G_i/o family. In the present mini-review, we focus on (i) the identification of functional selective OXT (oxytocin)-derived peptides capable of activating single G_i/o isoforms, namely G_i1 or G_i3; and (ii) the characterization of an SS (somatostatin) receptor SST5 mutant selectively impaired in its G_oA coupling. These analogues and receptor mutants represent unique tools for examining the contribution of G_i/o isoforms in complex biological responses and open the way for the development of drugs with peculiar selectivity profiles.