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

Activation of K+ channels by the G protein beta gamma 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 GABA(B) 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 G beta gamma subunits induces desensitization by uncoupling G beta gamma from the effector K+ channel. While receptor-free KCTD12 desensitizes K+ currents activated by other GPCRs in vitro, native KCTD12 is exclusively associated with GABA(B) receptors. Accordingly, genetic ablation of KCTD12 specifically alters GABA(B) responses in the brain. Our results show that GABA(B) receptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts G beta gamma signaling.