Auxiliary GABABReceptor Subunits Uncouple G Protein [beta][gamma] Subunits from Effector Channels to Induce Desensitization

Activation 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 GABABreceptor 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 GABABreceptors. Accordingly, genetic ablation of KCTD12 specifically alters GABABresponses in the brain. Our results show that GABABreceptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts Gβγ signaling.