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 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.

Department of Biomedicine University of Basel Klingelbergstrasse 50 70 CH 4056 Basel Switzerland

Department of Biomedicine University of Basel Klingelbergstrasse 50 70 CH 4056 Basel Switzerland; Institute of Experimental Medicine ASCR Vídeňská 1083 14220 Prague 4 Krč Czech Republic

Institute of Physiology University of Freiburg Hermann Herderstrasse 7 79104 Freiburg Germany

Institute of Physiology University of Freiburg Hermann Herderstrasse 7 79104 Freiburg Germany; Center for Biological Signalling Studies Albertstrasse 10 79108 Freiburg Germany

Citace poskytuje Crossref.org

The role of GABAB receptors in the subcortical pathways of the mammalian auditory system

Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing

KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents

GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization