Activating G _αi2 mutations inhibit AC’s production of cAMP. (A) Following GPCR stimulation, GTP-bound G_αs subunits promote (1), while GTP-bound G_αi subunits oppose (2), AC production of cAMP from ATP. The net balance of G_αs and the G_αi activities dictates the level of cAMP produced, which then functions as a second messenger to regulate various cellular responses (3). The extent of cAMP inhibition is limited by the normal cycling of WT G_αi2 proteins into their inactive GDP-bound state (4). (B) Prolonged cycling of activating mutant G_αi2 proteins in the patients’ cells disproportionately inhibits AC (1), thereby decreasing intracellular cAMP levels (2), which results in decreased downstream signaling (3). This may be responsible for other facets of the patients’ clinical features, such as impaired endocrine responses.