Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24836506
DOI
10.1016/j.neuron.2014.04.015
PII: S0896-6273(14)00305-5
Knihovny.cz E-resources
- MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism MeSH
- HEK293 Cells MeSH
- Intracellular Signaling Peptides and Proteins metabolism MeSH
- Humans MeSH
- Brain metabolism MeSH
- Mice MeSH
- GTP-Binding Protein beta Subunits metabolism MeSH
- GTP-Binding Protein gamma Subunits metabolism MeSH
- Receptors, GABA-B chemistry metabolism MeSH
- Receptors, GABA metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- G Protein-Coupled Inwardly-Rectifying Potassium Channels MeSH
- Intracellular Signaling Peptides and Proteins MeSH
- pfetin protein, mouse MeSH Browser
- GTP-Binding Protein beta Subunits MeSH
- GTP-Binding Protein gamma Subunits MeSH
- Receptors, GABA-B MeSH
- Receptors, GABA MeSH
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 Physiology University of Freiburg Hermann Herderstrasse 7 79104 Freiburg Germany
References provided by 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
GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization
