Auxiliary GABAB Receptor Subunits Uncouple G Protein βγ Subunits from Effector Channels to Induce Desensitization

•KCTD8, KCTD12, and KCTD16 proteins bind to G protein βγ subunits•KCTD12 uncouples βγ subunits from K+ channels to desensitize the current response•KCTD12 protein in the brain is exclusively associated with GABAB receptors•GABAB receptors produce receptor-specific desensitization by harnessing KCTD12

SummaryActivation of K+ channels by the G protein βγ subunits is an important signaling mechanism of G-protein-coupled receptors. Typically, receptor-activated K+ currents desensitize in the sustained presence of agonists to avoid excessive effects on cellular activity. The auxiliary GABAB receptor subunit KCTD12 induces fast and pronounced desensitization of the K+ current response. Using proteomic and electrophysiological approaches, we now show that KCTD12-induced desensitization results from a dual interaction with the G protein: constitutive binding stabilizes the heterotrimeric G protein at the receptor, whereas dynamic binding to the receptor-activated Gβγ subunits induces desensitization by uncoupling Gβγ from the effector K+ channel. While receptor-free KCTD12 desensitizes K+ currents activated by other GPCRs in vitro, native KCTD12 is exclusively associated with GABAB receptors. Accordingly, genetic ablation of KCTD12 specifically alters GABAB responses in the brain. Our results show that GABAB receptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts Gβγ signaling.