Mechanism of GABAB Receptor desensitization - KCTD-action on G Protein βγ Subunits

Tureczek R, Schwenk J, Fritzius T, Ivanova K, Zolles G, Adelfinger L, Jacquier V, Besseyrias V, Gassmann M, Schulte U, Fakler B, Bettler B

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 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 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 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 Gβγ signaling.

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