Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization.

Turecek R; Schwenk J; Fritzius T; Ivankova K; Zolles G; Adelfinger L; Jacquier V; Besseyrias V; Gassmann M; Schulte U; Fakler B; Bettler B

doi:10.1016/j.neuron.2014.04.015

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Journal article

Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization.

Turecek R 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.
Schwenk J Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany; Center for Biological Signalling Studies (BIOSS), Albertstrasse 10, 79108 Freiburg, Germany.
Fritzius T Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Ivankova K Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Zolles G Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany.
Adelfinger L Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Jacquier V Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Besseyrias V Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Gassmann M Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Schulte U Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany; Center for Biological Signalling Studies (BIOSS), Albertstrasse 10, 79108 Freiburg, Germany.
Fakler B Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany; Center for Biological Signalling Studies (BIOSS), Albertstrasse 10, 79108 Freiburg, Germany. Electronic address: bernd.fakler@physiologie.uni-freiburg.de.
Bettler B Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland. Electronic address: bernhard.bettler@unibas.ch.

2014-05-20

Published in:

Neuron. - 2014

G Protein-Coupled Inwardly-Rectifying Potassium Channels

GTP-Binding Protein beta Subunits

GTP-Binding Protein gamma Subunits

Intracellular Signaling Peptides and Proteins

English 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.

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