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Auxiliary GABAB receptor subunits uncouple G protein betagamma subunits from effector channels to induce desensitization
Journal
Neuron
Volume
82
Number
5
Pages / Article-Number
1032-44
Keywords
Animals; Brain/metabolism; CHO Cells; Cricetulus; G Protein-Coupled Inwardly-Rectifying Potassium Channels/*metabolism; GTP-Binding Protein beta Subunits/*metabolism; GTP-Binding Protein gamma Subunits/*metabolism; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins/metabolism; Mice; Receptors, GABA/*metabolism; Receptors, GABA-B/chemistry/*metabolism
Mesh terms
Animals; Brain, metabolism; CHO Cells; Cricetulus; G Protein-Coupled Inwardly-Rectifying Potassium Channels, metabolism; GTP-Binding Protein beta Subunits, metabolism; GTP-Binding Protein gamma Subunits, metabolism; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins, metabolism; Mice; Receptors, GABA, metabolism; Receptors, GABA-B, metabolism
Abstract
Activation of K(+) channels by the G protein betagamma 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 Gbetagamma subunits induces desensitization by uncoupling Gbetagamma 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 Gbetagamma signaling.