GABAB receptors: synaptic functions and mechanisms of diversity

Ulrich, Daniel; Bettler, Bernhard

doi:10.1016/j.conb.2007.04.001

Cited by 172 publications

(125 citation statements)

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“…These effects may require longer washout times to return to control values. Since GABA release may activate both presynaptic and postsynaptic GABA B receptors (Ulrich and Bettler, 2007), we also preliminarily tested the effects of the GABA B antagonist ethylamino]-2-hydroxypropyl]phosphinic acid; 1 M) on recurrent SLEs in six isolated hippocampi. Similar to the GABA A antagonist results, the preictal duration decreased by 57.3% (p ϭ 0.022), and the interictal duration decreased by 68.3% (p ϭ 0.008), whereas the ictal duration was not significantly decreased.…”

Section: Resultsmentioning

confidence: 99%

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Zhang¹,

Koifman²,

Shin³

et al. 2012

J. Neurosci.

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How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg 2ϩ /high-K ϩ perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a "preictal phase," which abruptly turns into a higher frequency "ictal" phase. Blockade of GABA A receptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABA A responses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABA A reversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.

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Section: Resultsmentioning

confidence: 99%

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Zhang¹,

Koifman²,

Shin³

et al. 2012

J. Neurosci.

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“…GIRK cells and hippocampal neurons (14)(15)(16)(17)(18)(19)(20)(21) were imaged and analyzed as described previously (20) using ImageJ (version 1.40g) and Origin (version 6; OriginLab).…”

Section: Methodsmentioning

confidence: 99%

“…Heteromers formed from R1aR2 and R1bR2 are thought to play distinct roles in neurotransmission (13)(14)(15)(16)(17)(18), with R1aR2 contributing to presynaptic heteroreceptors to inhibit neurotransmitter release, although both R1aR2 and R1bR2 populate postsynaptic membranes to dampen excitability. These heteromeric subtypes exhibit different subcellular compartmentalization with the SDs acting as an axonal-targeting sequence to deliver R1aR2 more efficiently to axons compared with R1bR2 (19).…”

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confidence: 99%

Sushi domains confer distinct trafficking profiles on GABA _B receptors

Hannan

Wilkins

Smart

2012

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

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GABA B receptors mediate slow inhibitory neurotransmission in the brain and feature during excitatory synaptic plasticity, as well as various neurological conditions. These receptors are obligate heterodimers composed of GABA B R1 and R2 subunits. The two predominant R1 isoforms differ by the presence of two complement control protein modules or Sushi domains (SDs) in the N terminus of R1a. By using live imaging, with an α-bungarotoxin-binding site (BBS) and fluorophore-linked bungarotoxin, we studied how R2 stabilizes R1b subunits at the cell surface. Heterodimerization with R2 reduced the rate of internalization of R1b, compared with R1b homomers. However, R1aR2 heteromers exhibited increased cell surface stability compared with R1bR2 receptors in hippocampal neurons, suggesting that for receptors containing the R1a subunit, the SDs play an additional role in the surface stability of GABA B receptors. Both SDs were necessary to increase the stability of R1aR2 because single deletions caused the receptors to be internalized at the same rate and extent as R1bR2 receptors. Consistent with these findings, a chimera formed from the metabotropic glutamate receptor (mGluR)2 and the SDs from R1a increased the surface stability of mGluR2. These results suggest a role for SDs in stabilizing cell surface receptors that could impart different pre-and postsynaptic trafficking itineraries on GABA B receptors, thereby contributing to their physiological and pathological roles. underlying slow GABA-mediated inhibitory neurotransmission (1) that regulates neuronal excitability (2-4). These receptors are increasingly considered as potential therapeutic targets for a range of diseases, including epilepsy, schizophrenia, anxiety, depression, and substance abuse (1, 5). Functional GABA B receptors are heteromers formed from GABA B R1 subunits containing the agonist binding domain (6) and R2 subunits that link to G protein signaling (7,8).To date, just one isoform of the R2 subunit has been reported (9, 10), whereas several isoforms of the R1 subunit exist [R1a, R1b, R1c, R1e, R1j (1)]. Among these, R1a and R1b predominate in the central nervous system (CNS), and their expression arises by the use of different promoters (11) of the GABBR1 gene. R1a subunits contain 143 aa forming two Sushi domains (SDs) in the N terminus, which are also known as complement control proteins or short consensus repeats (12). These SDs are absent in R1b being replaced by 18 unique amino acids.Heteromers formed from R1aR2 and R1bR2 are thought to play distinct roles in neurotransmission (13-18), with R1aR2 contributing to presynaptic heteroreceptors to inhibit neurotransmitter release, although both R1aR2 and R1bR2 populate postsynaptic membranes to dampen excitability. These heteromeric subtypes exhibit different subcellular compartmentalization with the SDs acting as an axonal-targeting sequence to deliver R1aR2 more efficiently to axons compared with R1bR2 (19). This would, in part, explain the differential pre-and postsynaptic signaling properties o...

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“…Molecular diversity in the GABA B system arises from the GABA B1a and GABA B1b subunit isoforms, both of which combine with GABA B2 subunits to form heteromeric GABA B(1a,2) and GABA B(1b,2) receptors (8). Genetically modified mice revealed that the two receptors convey nonredundant synaptic functions at glutamatergic synapses, owing to their differing distribution to axonal and dendritic compartments (3,9). Selectively GABA B(1a,2) receptors control the release of glutamate, whereas predominantly GABA B(1b,2) receptors activate postsynaptic Kir3 channels in dendritic spines (10)(11)(12).…”

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confidence: 99%

“…They are therapeutic targets for a variety of disorders, including cognitive impairments, addiction, anxiety, depression, and epilepsy (1). Depending on their subcellular localization GABA B receptors exert distinct regulatory effects on synaptic transmission (2)(3)(4). Presynaptic GABA B receptors inhibit neurotransmitter release (5,6).…”

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confidence: 99%

NMDA receptor-dependent GABA _B receptor internalization via CaMKII phosphorylation of serine 867 in GABA _B1

Guetg

Aziz

Holbro

et al. 2010

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

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GABA B receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GABA B receptors are abundant on dendritic spines, where they dampen postsynaptic excitability and inhibit Ca 2+ influx through NMDA receptors when activated by spillover of GABA from neighboring GABAergic terminals. Here, we show that an excitatory signaling cascade enables spines to counteract this GABA B -mediated inhibition. We found that NMDA application to cultured hippocampal neurons promotes dynamindependent endocytosis of GABA B receptors. NMDA-dependent internalization of GABA B receptors requires activation of Ca 2+ /Calmodulindependent protein kinase II (CaMKII), which associates with GABA B receptors in vivo and phosphorylates serine 867 (S867) in the intracellular C terminus of the GABA B1 subunit. Blockade of either CaMKII or phosphorylation of S867 renders GABA B receptors refractory to NMDA-mediated internalization. Time-lapse two-photon imaging of organotypic hippocampal slices reveals that activation of NMDA receptors removes GABA B receptors within minutes from the surface of dendritic spines and shafts. NMDA-dependent S867 phosphorylation and internalization is predominantly detectable with the GABA B1b subunit isoform, which is the isoform that clusters with inhibitory effector K + channels in the spines. Consistent with this, NMDA receptor activation in neurons impairs the ability of GABA B receptors to activate K + channels. Thus, our data support that NMDA receptor activity endocytoses postsynaptic GABA B receptors through CaMKIImediated phosphorylation of S867. This provides a means to spare NMDA receptors at individual glutamatergic synapses from reciprocal inhibition through GABA B receptors.γ-aminobutyric acid | spines | trafficking | synaptic plasticity | GABAB

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GABAB receptors: synaptic functions and mechanisms of diversity

Cited by 172 publications

References 50 publications

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Sushi domains confer distinct trafficking profiles on GABA _B receptors

NMDA receptor-dependent GABA _B receptor internalization via CaMKII phosphorylation of serine 867 in GABA _B1

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GABAB receptors: synaptic functions and mechanisms of diversity

Cited by 172 publications

References 50 publications

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Sushi domains confer distinct trafficking profiles on GABA B receptors

NMDA receptor-dependent GABA B receptor internalization via CaMKII phosphorylation of serine 867 in GABA B1

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Sushi domains confer distinct trafficking profiles on GABA _B receptors

NMDA receptor-dependent GABA _B receptor internalization via CaMKII phosphorylation of serine 867 in GABA _B1