Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

Cathomas, Flurin; Sigrist, Hannes; Schmid, Luca; Seifritz, Erich; Gassmann, Martin; Bettler, Bernhard; Pryce, Christopher R.

doi:10.1016/j.bbr.2016.10.006

Cited by 14 publications

(11 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20,21 Accordingly, considerable evidence suggests that this protein−protein interaction (PPI) could serve as a potential target for subtle modulation of GBR responses. 22,23 However, how dysfunctional KCTD/GBR signaling translates into neuropsychiatric disorders is not well understood. Hence, we aimed to explore the KCTD/GBR PPI by developing compounds specifically targeting this protein complex, thereby potentially allowing precise and temporal control of GBR function.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The association of the KCTD proteins with the GBR stabilizes the G protein at the receptor and influences effector K + and Ca 2+ channels. ,, KCTD/GBR complexes possess distinct kinetic and functional properties with potential implications for neuropsychiatric diseases, including bipolar and depressive disorders, which could be linked to dysfunction of KCTDs. , Accordingly, considerable evidence suggests that this protein–protein interaction (PPI) could serve as a potential target for subtle modulation of GBR responses. , However, how dysfunctional KCTD/GBR signaling translates into neuropsychiatric disorders is not well understood. Hence, we aimed to explore the KCTD/GBR PPI by developing compounds specifically targeting this protein complex, thereby potentially allowing precise and temporal control of GBR function.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting the γ-Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

et al. 2019

Self Cite

View full text Add to dashboard Cite

Targeting multiprotein receptor complexes, rather than receptors directly, is a promising concept in drug discovery. This is particularly relevant to the GABAB receptor complex, which plays a prominent role in many brain functions and diseases. Here, we provide the first studies targeting a key protein–protein interaction of the GABAB receptor complexthe interaction with KCTD proteins. By employing the μSPOT technology, we first defined the GABAB receptor-binding epitope mediating the KCTD interaction. Subsequently, we developed a highly potent peptide-based inhibitor that interferes with the KCTD/GABAB receptor complex and efficiently isolates endogenous KCTD proteins from mouse brain lysates. X-ray crystallography and SEC-MALS revealed inhibitor induced oligomerization of KCTD16 into a distinct hexameric structure. Thus, we provide a template for modulating the GABAB receptor complex, revealing a fundamentally novel approach for targeting GABAB receptor-associated neuropsychiatric disorders.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting the γ-Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…To generate KCTD12 À/À and KCTD16 À/À mice expressing channelrhodopsin 2 (ChR2) coupled to an enhanced yellow fluorescent protein (EYFP) under control of the vesicular GABA transporter (VGAT) promoter in GABAergic neurons, the VGAT-ChR2(H134R)-EYFP transgene (Zhao et al, 2011) was crossed into the previously described KCTD12 À/À and KCTD16 À/À mouse lines (Metz et al, 2011;Cathomas et al, 2015Cathomas et al, , 2017. GABA B1a À/À and GABA B1b À/À mice were bred as reported earlier (Vigot et al, 2006).…”

Section: Mice and Tissue Preparationmentioning

confidence: 99%

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

et al. 2018

Self Cite

View full text Add to dashboard Cite

a b s t r a c tFollowing the discovery of GABA B receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABA B receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABA B1a , GABA B1b and GABA B2 form two heterodimeric GABA B(1a,2) and GABA B(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K þ channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABA B(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABA B(1a,2) receptors function as heteroreceptors and inhibit glutamate release. Both GABA B(1a,2) and GABA B(1b,2) receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABA B receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABA B receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABA B(1a,2) and GABA B(1b,2) receptors on spindle oscillations. We found that selectively GABA B(1a,2) heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABA B(1b,2) receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABA B(1a,2) and GABA B(1b,2) receptors.

show abstract

“…In genetic studies, the KCTD12 gene has been associated with major depressive disorder, bipolar disease, and schizophrenia (24,25). Mice lacking KCTD12 or KCTD16 exhibit altered fear memory relative to wild-type mice (22,26,27). Thus, molecular interaction of these KCTD proteins with GABA B receptors is important for the normal function of inhibitory brain circuits.…”

mentioning

confidence: 99%

Structural basis for auxiliary subunit KCTD16 regulation of the GABA _B receptor

Zuo

Glaaser

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Metabotropic GABA B receptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABA B receptor complexes contain the principal subunits GABA B1 and GABA B2 , which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABA B receptors and modify the kinetics of GABA B receptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABA B receptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABA B2 receptor. A single GABA B2 Cterminal peptide is bound to the interior of an open pentamer formed by the oligomerization domain of five KCTD16 subunits. Mutation of specific amino acids identified in the structure of the GABA B2 -KCTD16 interface disrupted both the biochemical association and functional modulation of GABA B receptors and G protein-activated inwardly rectifying K + channel (GIRK) channels. These interfacial residues are conserved among KCTDs, suggesting a common mode of KCTD interaction with GABA B receptors. Defining the binding interface of GABA B receptor and KCTD reveals a potential regulatory site for modulating GABA B -receptor function in the brain. GABA B receptor | KCTD | principal and auxiliary subunits | crystal structure M etabotropic γ-aminobutyric acid (GABA) type B (GABA B )receptors are implicated in various neurological and psychiatric disorders, including spasticity, epilepsy, depression, addiction, and anxiety (1-3). GABA B receptors provide a crucial component of inhibitory neurotransmission in the nervous system (1-3), via coupling to G i/o type G proteins that modulate three different downstream effectors: voltage-gated Ca 2+ channels, G proteinactivated inwardly rectifying K + (GIRK) channels, and adenylyl cyclase (1-3). The GABA B receptor functions as an obligatory heterodimer, consisting of the GABA B1 and GABA B2 subunits (4-9), whereby the GABA B1 subunit binds orthosteric ligand (10, 11) and the GABA B2 subunit couples to the G protein (12)(13)(14)(15)(16)(17)(18).Recent proteomic studies led to the discovery of a family of auxiliary proteins for the GABA B receptor, originally referred to as potassium channel tetramerization domain-containing (KCTD) proteins (19)(20)(21). A subset of KCTD proteins (numbered 8, 12, 12b, and 16) interact with the cytoplasmic tail of the GABA B2 subunit (3, 20, 21) and convey unique functional properties to the signaling of the GABA B receptor (3). For example, expression of each of the four KCTD proteins leads to acceleration of GABA B receptordependent activation of GIRK currents, albeit to different extents (20,22). KCTD12 and KCTD12b also promote rapid desensitization of the GABA B receptor-induced GIRK current, by uncoupling Gβγ from GIRK channels (20,22,23). By contrast, KCTD8 and KCTD16 generate primarily nondesensitizing receptor responses (20,22...

show abstract

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

Cited by 14 publications

References 54 publications

Targeting the γ-Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

Targeting the γ-Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

Structural basis for auxiliary subunit KCTD16 regulation of the GABA _B receptor

Contact Info

Product

Resources

About

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

Cited by 14 publications

References 54 publications

Targeting the γ-Aminobutyric Acid Type B (GABAB) Receptor Complex: Development of Inhibitors Targeting the K+ Channel Tetramerization Domain (KCTD) Containing Proteins/GABAB Receptor Protein–Protein Interaction

Targeting the γ-Aminobutyric Acid Type B (GABAB) Receptor Complex: Development of Inhibitors Targeting the K+ Channel Tetramerization Domain (KCTD) Containing Proteins/GABAB Receptor Protein–Protein Interaction

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

Structural basis for auxiliary subunit KCTD16 regulation of the GABA B receptor

Contact Info

Product

Resources

About

Targeting the γ-Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

Targeting the γ-Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

Structural basis for auxiliary subunit KCTD16 regulation of the GABA _B receptor