Activating G _αi2 mutations impair G protein cycling for GPCR signaling. (A) Normal WT G_α: GPCR ligation (1) activates heterotrimeric G proteins by exchanging GTP for GDP on the G_α subunit (2), causing G_α disassociation from the G_βγ heterodimer (3), and initiating downstream signaling (4) for cellular responses such as cell migration in the case of G_αi2 (5). To terminate signaling, G_α uses its GTPase activity to hydrolyze GTP into GDP (6), allowing the inactivated G_α to reassemble into the G_αβγ heterotrimer and reassociate with a GPCR (7) for a new activation cycle. (B) Mutant G_α: activating mutations in G_αi2 impair hydrolysis of G_αi2-bound GTP (1), delaying conversion of G_αi2 back into its inactive GDP-bound form (2) and hence G_αi2 reassociation with the G_βγ heterodimer and GPCR (3). The chronic decoupling of the heterotrimeric G proteins from GPCRs (4) impairs responses to GPCR ligands such as chemokine receptor–mediated migration (5).