Auxiliary GABAB receptor subunits uncouple G protein βγ 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 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; Institute of Experimental Medicine, ASCR, Vídeňská 1083, 14220 Prague 4-Krč, Czech Republic.
Rostislav
R
Turecek
Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany; Center for Biological Signalling Studies (BIOSS), Albertstrasse 10, 79108 Freiburg, Germany.
Jochen
J
Schwenk
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Thorsten
T
Fritzius
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Klara
K
Ivankova
Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany.
Gerd
G
Zolles
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Lisa
L
Adelfinger
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Valerie
V
Jacquier
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Valerie
V
Besseyrias
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Martin
M
Gassmann
Institute of Physiology, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany; Center for Biological Signalling Studies (BIOSS), Albertstrasse 10, 79108 Freiburg, Germany.
Uwe
U
Schulte
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.
Bernd
B
Fakler
Department of Biomedicine, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland. Electronic address: bernhard.bettler@unibas.ch.
Bernhard
B
Bettler
D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018079:Receptors, GABA / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000737:chemistry / Q000378:metabolism*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D047908:Intracellular Signaling Peptides and Proteins; D018079:Receptors, GABA; D018080:Receptors, GABA-B; C493176:pfetin protein, mouse