Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics

Schwenk, Jochen M.; Pérez-Garci, Enrique; Schneider, Andy; Kollewe, Astrid; Gauthier-Kemper, Anne; Fritzius, Thorsten; Raveh, Adi; Dinamarca, Margarita C.; Hanuschkin, Alexander; Bildl, Wolfgang; Klingauf, Jürgen; Gassmann, Martin; Schulte, Uwe; Bettler, Bernhard; Fakler, Bernd

doi:10.1038/nn.4198

Cited by 130 publications

(188 citation statements)

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“…The KCTD subunits influence activation/deactivation kinetics and desensitization of the receptor response (Fritzius et al, 2017;Turecek et al, 2014). Moreover, KCTD16 was shown to scaffold effector Ca 2þ and hyperpolarization-activated cyclic nucleotide gated (HCN) channels at the receptor (Schwenk et al, 2016). Knock-out mice demonstrated that KCTD12 and KCTD16 modulate the postsynaptic GABA B receptor response and alter the duration of sIPSCs (Booker et al, 2017;Fritzius et al, 2017;Schwenk et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

et al. 2018

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“…As such, it is well placed to influence GABA B modulation of neuronal excitability, oscillatory network activity, and cognitive functions such as learning and memory [42][43][44][45]. The different behavioural phenotypes that can be attributed to KCTD16 (present study) and KCTD12 [39] coincide with their distinct domain structures and to their being constituents of distinct receptor complexes [41,57]. As a group and individually, therefore, evidence is emerging that auxillary KCTD subunits of GABA B receptors are of regulatory relevance to specific learning and memory processes that are important in adaptive behaviour and that also underlie important psychopathologies in neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 49%

“…The auxillary subunit KCTD16, which as noted above is highly expressed in a number of brain regions including amygdala and hippocampus [40], regulates the GABA B receptors with respect to their gating of postsynaptic ion channels, such as hyperpolarization-activated cyclic nucleotide gated (HCN) channels [6,41]. As such, it is well placed to influence GABA B modulation of neuronal excitability, oscillatory network activity, and cognitive functions such as learning and memory [42][43][44][45].…”

Section: Discussionmentioning

confidence: 99%

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Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

Cathomas

Sigrist

Schmid

et al. 2017

Behavioural Brain Research

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Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABAB receptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABAB receptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12(-/-)) exhibit increased auditory fear learning and that Kctd12(+/-) mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABAB receptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16(-/-) and Kctd16(+/-) mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16(-/-) and Kctd16(+/-) mice. When fear memory was tested on the following day, Kctd16(-/-) mice exhibited less extinction of auditory fear memory relative to WT and Kctd16(+/-) mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16(+/-) mice. Relative to WT, both Kctd16(+/-) and Kctd16(-/-) mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABAB receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders.

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“…The possible mechanisms may involve NMDA receptor, which often participates in long-lasting plastic changes and has been shown to control trafficking and surface expression of GABAbR via the CaMKII-AMPK phosphorylation cascade (Guetg et al, 2010;Maier et al, 2010;Terunuma et al, 2010). Changing GABAbR kinetics properties by the KCTD family of axillary proteins (Gassmann and Bettler, 2012;Schwenk et al, 2010) or modulation via several recently discovered interacting proteins (Schwenk et al, 2016) may also be involved. Some of these mechanisms have been documented in dendrites of glutamatergic neurons but remain to be tested in GABAergic terminals.…”

Section: Gababr-dependent Alterations In Pv-in and Som-in Inputs To Lmentioning

confidence: 99%

GABAb Receptor Mediates Opposing Adaptations of GABA Release From Two Types of Prefrontal Interneurons After Observational Fear

Liu

Ito

Morozov

2016

Neuropsychopharmacol

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The observational fear (OF) paradigm in rodents, in which the subject is exposed to a distressed conspecific, elicits contextual fear learning and enhances future passive avoidance learning, which may model certain behavioral traits resulting from traumatic experiences in humans. As these behaviors affected by the OF require dorso-medial prefrontal cortex (dmPFC), we searched for synaptic adaptations in dmPFC resulting from OF in mice by recording synaptic responses in dmPFC layer V pyramidal neurons elicited by repeated 5 Hz electrical stimulation of dmPFC layer I or by optogenetic stimulation of specific interneurons ex vivo 1 day after OF. OF increased depression of inhibitory postsynaptic currents (IPSCs) along IPSC trains evoked by the 5 Hz electrical stimulation, but, surprisingly, decreased depression of dendritic IPSCs isolated after blocking GABAa receptor on the soma. Subsequent optogenetic analyses revealed increased depression of IPSCs originating from perisomatically projecting parvalbumin interneurons (PV-IPSCs), but decreased depression of IPSCs from dendritically projecting somatostatin cells (SOM-IPSCs). These changes were no longer detectable in the presence of a GABAb receptor antagonist CGP52432. Meanwhile, OF decreased the sensitivity of SOM-IPSCs, but not PV-IPSCs to a GABAb receptor agonist baclofen. Thus, OF causes opposing changes in GABAb receptor mediated suppression of GABA release from PV-positive and SOM-positive interneurons. Such adaptations may alter dmPFC connectivity with brain areas that target its deep vs superficial layers and thereby contribute to the behavioral consequences of the aversive experiences.

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Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics

Cited by 130 publications

References 48 publications

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

GABAb Receptor Mediates Opposing Adaptations of GABA Release From Two Types of Prefrontal Interneurons After Observational Fear

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