Metabotropic Gamma-aminobutyric Acid Receptors Research Articles

Components of the GABAergic signaling in the peripheral cholinergic synapses of vertebrates: a review.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian central nervous system. Since the 1970s, many studies have focused on the role of GABA in the mammalian peripheral nervous system, and particularly in the cholinergic synapses. In this review, we present current findings for the cholinergic neurons of vegetative ganglia as well as for the neurons innervating smooth and striated muscles. Synaptic contacts formed by these neurons contain GABA and the enzyme, glutamic acid decarboxylase, which catalyzes the synthesis of GABA from glutamate. Newly formed GABA is released in the cholinergic synapses and mostly all the peripheral cholinergic synaptic contacts contain iono- and metabotropic GABA receptors. Although the underlying molecular mechanism of the release is not well understood, still, it is speculated that GABA is released by a vesicular and/or non-vesicular way via reversal of the GABA transporter. We also review the signaling role of GABA in the peripheral cholinergic synapses by modulating acetylcholine release, but its exact physiological function remains to be elucidated.

Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

Kohlschutter-Tönz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS.

A Gut Feeling about GABA: Focus on GABAB Receptors

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract.

Gamma‐aminobutyric acid (GABA)‐mediated neural connections in the Drosophila antennal lobe

Inhibitory synaptic connections mediated by gamma-aminobutyric acid (GABA) play important roles in the neural computation of the brain. To obtain a detailed overview of the neural connections mediated by GABA signals, we analyzed the distribution of the cells that produce and receive GABA in the Drosophila adult brain. Relatively small numbers of the cells, which form clusters in several areas of the brain, express the GABA synthesis enzyme Gad1. On the other hand, many cells scattered across the brain express ionotropic GABA(A) receptor subunits (Lcch3 and Rdl) and metabotropic GABA(B) receptor subtypes (GABA-B-R1, -2, and -3). To analyze the expression of these genes in distinct identified cell types, we focused on the antennal lobe, where GABAergic neurons play important roles in odor coding. By combining fluorescent in situ hybridization and immunolabeling against GFP expressed with cell-type-specific GAL4 driver strains, we quantified the percentage of the cells that produce or receive GABA for each cell type. GABA was synthesized in the middle antennocerebral tract (mACT) projection neurons and two types of local neurons. Among them, mACT neurons had few presynaptic sites in the antennal lobe, making the local neurons essentially the sole provider of GABA signals there. On the other hand, not only these local neurons but also all types of projection neurons expressed both ionotropic and metabotropic GABA receptors. Thus, even though inhibitory signals are released from only a few, specific types of local neurons, the signals are read by most of the neurons in the antennal lobe neural circuitry.

Neurogenesis Mediated by γ-Aminobutyric Acid and Glutamate Signaling

In this review, we will summarize our ongoing studies on the functionality of both gamma-aminobutyric acid (GABA) and glutamate receptors expressed by undifferentiated neural progenitor cells isolated from embryonic rodent brains. Cells were cultured with growth factors for the formation of round spheres by clustered cells under floating conditions, whereas a reverse transcription polymerase chain reaction analysis revealed expression of mRNA for particular subtypes of different ionotropic and metabotropic GABA and glutamate receptors in undifferentiated progenitors and neurospheres. Moreover, sustained exposure to either GABAergic or glutamatergic agonists not only modulated the size of neurospheres formed, but also affected spontaneous and induced differentiation of neural progenitor cells into particular progeny cell lineages such as neurons and astroglia. Both GABA and glutamate could play a pivotal role in the mechanisms underlying proliferation for self-replication along with the determination of subsequent differentiation fate toward particular progeny lineages through activation of their receptor subtypes functionally expressed by undifferentiated neural progenitor cells. Accordingly, neurogenesis seems to be also under control by GABAergic and glutamatergic signaling in developing brains as seen with neurotransmission in adult brains.

Photothrombosis ischemia stimulates a sustained astrocytic Ca2+ signaling in vivo

Although there is significant information concerning the consequences of cerebral ischemia on neuronal function, relatively little is known about functional responses of astrocytes, the predominant glial-cell type in the central nervous system. In this study, we asked whether focal ischemia would impact astrocytic Ca(2+) signaling, a characteristic form of excitability in this cell type. In vivo Ca(2+) imaging of cortical astrocytes was performed using two-photon (2-P) microscopy during the acute phase of photothrombosis-induced ischemia initiated by green light illumination of circulating Rose Bengal. Although whisker evoked potentials were reduced by over 90% within minutes of photothrombosis, astrocytes in the ischemic core remained structurally intact for a few hours. In vivo Ca(2+) imaging showed that an increase in transient Ca(2+) signals in astrocytes within 20 min of ischemia. These Ca(2+) signals were synchronized and propagated as waves amongst the glial network. Pharmacological manipulations demonstrated that these Ca(2+) signals were dependent on activation of metabotropic glutamate receptor 5 (mGluR5) and metabotropic gamma-aminobutyric acid receptor (GABA(B)R) but not by P2 purinergic receptor or A1 adenosine receptor. Selective inhibition of Ca(2+) in astrocytes with BAPTA significantly reduced the infarct volume, demonstrating that the enhanced astrocytic Ca(2+) signal contributes to neuronal damage presumably through Ca(2+)-dependent release of glial glutamate. Because astrocytes offer multiple functions in close communication with neurons and vasculature, the ischemia-induced increase in astrocytic Ca(2+) signaling may represent an initial attempt for these cells to communicate with neurons or provide feed back regulation to the vasculature.

Cellular and subcellular localization of the GABAB receptor 1a/b subunit in the rat periaqueductal gray matter

The inhibitory effects of gamma-aminobutyric acid (GABA)ergic neurotransmission in the periaqueductal gray matter (PAG) are mediated, at least partly, by metabotropic GABA(B) receptor subtypes whose cellular and subcellular localization is still unknown. We performed immunohistochemical experiments with an antibody against GABA(B) receptor subtype 1a/b (GABA(B)R(1a/b)) by using light and electron microscopy. On light microscopy, GABA(B)R(1a/b) immunoreactivity (IR) was in all columns, defined by cytochrome oxidase histochemistry. Neuropil labeling was strongest in the lateral portion of dorsolateral PAG. Labeled neurons, albeit not numerous, were in ventrolateral, dorsal, and medial subdivisions and were sparser in dorsolateral PAG. Labeling was mostly on the soma of PAG neurons. Sometimes GABA(B)R(1a/b) IR spread along proximal dendrites; in these cases bipolar neurons were the most common type. On electron microscopy, GABA(B)R(1a/b) IR was mainly on dendrites (54.92% of labeled elements) and axon terminals (21.90%) making synapses with labeled and unlabeled postsynaptic elements. Presynaptic labeling was also on unmyelinated and myelinated axons (overall 8% of all labeled elements). Postsynaptically, GABA(B)R(1a/b) IR was at extrasynaptic sites on dendritic shafts; spines were always unlabeled. On axon terminals, GABA(B)R(1a/b) IR was on extrasynaptic membranes and sometimes on presynaptic membrane specializations. Of the labeled elements, 13.03% elements were distal astrocytic processes (dAsPs) surrounding both symmetric and asymmetric synapses whose pre- and postsynaptic elements were often labeled. Immunoreactive dAsPs were around the soma and dendrites of both labeled and unlabeled neurons. These findings provide insights into the intrinsic PAG organization and suggest that presynaptic, postsynaptic, and glial GABA(B) receptors may play crucial roles in controlling PAG neuronal activity.

Gamma-aminobutyric acid (GABA) and cell proliferation: focus on cancer cells.

In addition to its role in the adult mammalian nervous system as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is involved in the proliferation, differentiation, and migration of several kinds of cells including cancer cells. GABA is synthesized predominantly from glutamate by glutamate decarboxylase and exerts its effects via ionotropic GABA(A) receptors and/or metabotropic GABA(B) receptors. In this review, the current state of knowledge regarding the role of the GABAergic system in peripheral nonneuronal cell proliferation is described, and recent advances in elucidation of the mechanisms leading to cell proliferation are discussed.

Voltage‐gated Ca2+ channel subtypes mediating GABAergic transmission in the rat supraoptic nucleus

The supraoptic nucleus receives an abundant gamma-aminobutyric acid (GABA)ergic input which is inhibited by activation of various presynaptic metabotropic receptors. We here analysed the subtypes of voltage-gated Ca2+ channels intervening in the control of transmitter release at these synapses. To address this issue, we tested various specific inhibitors of Ca2+ channels on evoked inhibitory postsynaptic currents (IPSCs). Blocking N- and P-type voltage-gated Ca2+ channels with 1 micromomega-conotoxin-GVIA and 20 nmomega-agatoxin-IVA, respectively, dramatically reduced IPSC amplitude. Q- and L-type Ca2+ channels also contributed to GABAergic transmission, although to a lesser extent, as revealed by applications of 200 nmomega-agatoxin-IVA and of the dihydropyridines nifedipine (10 microm) and nimodipine (10 microm). Evoked IPSCs were insensitive to SNX-482 (300 nm), a blocker of some R-type Ca2+ channels. Analysis of selective blockade by the various antagonists suggested that multiple types of Ca2+ channels synergistically interact to trigger exocytosis at some individual GABA release sites. We next investigated whether inhibition of GABA release in response to the activation of metabotropic glutamate, GABA and adenosine receptors involved the modulation of these presynaptic Ca2+ channels. This was not the case, as the inhibitory actions of selective agonists of these receptors were unaffected by the presence of the different Ca2+ channel antagonists. This finding suggests that these metabotropic receptors modulate GABAergic transmission through a different mechanism, downstream of Ca2+ entry in the terminals, or upstream through the activation of K+ channels.

GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent.

There is an emerging body of data purporting a role of gamma-aminobutyric acid (GABA) in the pathophysiology of mood disorders. However, the role of metabotropic GABA(B) receptors in depression is not well defined. The modified forced swim test has recently emerged as an excellent tool to assess behaviorally the role of monoamines in antidepressant action. To assess the role of GABA(B) receptors in antidepressant-related behavior, we examined a number of selective GABA(B) receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABA(B) receptor antagonists CGP56433A [[3-{1-(S)-[{3-cyclohexylmethyl)hydroxy phosphinyl}-2-(S) hydroxy propyl]amino}ethyl]benzoic acid; 1-10 mg/kg] and [3-[[1-(S)-3-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; 3-10 mg/kg] had a similar profile to the selective serotonin reuptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABA(B) receptor-positive modulator GS39783 (10-40 mg/kg) did not display antidepressant-like activity in the modified forced swim test. To further assess the possible interaction between GABA(B) receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine. 5-Hydroxytryptamine depletion (>90%) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. Together, these data demonstrate that GABA(B) receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression.

Localization of the GABAB receptor 1a/b subunit relative to glutamatergic synapses in the dorsal cochlear nucleus of the rat.

Metabotropic gamma-aminobutyric acid receptors (GABA(B)) are involved in pre- and postsynaptic inhibitory effects upon auditory neurons and have been implicated in different aspects of acoustic information processing. To understand better the mechanisms by which GABA(B) receptors mediate their inhibitory effects, we used pre-embedding immunocytochemical techniques combined with quantification of immunogold particles to reveal the precise subcellular distribution of the GABA(B1) subunit in the rat dorsal cochlear nucleus. At the light microscopic level, GABA(B1) was detected in all divisions of the cochlear complex. The most intense immunoreactivity for GABA(B1) was found in the dorsal cochlear nucleus, whereas immunoreactivity in the anteroventral and posteroventral cochlear nuclei was very low. In the dorsal cochlear nucleus, a punctate labeling was observed in the superficial (molecular and fusiform cell) layers. At the electron microscopic level, GABA(B1) was found at both post- and presynaptic locations. Postsynaptically, GABA(B1) was localized mainly in the dendritic spines of presumed fusiform cells. Quantitative immunogold immunocytochemistry revealed that the highest concentration of GABA(B1) in the plasma membrane was in dendritic spines, followed by dendritic shafts and somata. Thus, the most intense immunoreactivity for GABA(B1) was observed in dendritic spines with a high density of immunogold particles at extrasynaptic sites, peaking around 300 nm from glutamatergic synapses. This is in contrast to GABAergic synapses, in which GABA(B1) was only occasionally found. Presynaptically, receptor immunoreactivity was detected primarily in axospinous endings, probably from granule cells, in both the active zone and extrasynaptic sites. The localization of GABA(B1) relative to synaptic sites in the DCN suggests a role for the receptor in the regulation of dendritic excitability and excitatory inputs.

Chemical coding of GABA(B) receptor-immunoreactive neurones in hypothalamic regions regulating body weight.

Gamma-aminobutyric acid (GABA) interacts with hypothalamic neuronal pathways regulating feeding behaviour. GABA has been reported to stimulate feeding via both ionotropic GABA(A) and metabotropic GABA(B) receptors. The functional form of the GABA(B) receptor is a heterodimer consisting of GABA(B) receptor-1 (GABA(B)R1) and GABA(B) receptor-2 (GABA(B)R2) proteins. Within the heterodimer, the GABA-binding site is localized to GABA(B)R1. In the present study, we used an antiserum to the GABA(B)R1 protein in order to investigate the cellular localization of GABA(B)R1-immunoreactive neurones in discrete hypothalamic regions implicated in the control of body weight. The colocalization of GABA(B)R1 immunoreactivity with different chemical messengers that regulate food intake was analysed. GABA(B)R1-immunoreactive cell bodies were found in the periventricular, paraventricular (PVN), supraoptic, arcuate, ventromedial hypothalamic, dorsomedial hypothalamic, tuberomammillary nuclei and lateral hypothalamic area (LHA). Direct double-labelling showed that glutamic acid decarboxylase (GAD)-positive terminals were in close contact with GABA(B)R1-containing cell bodies located in all these regions. In the ventromedial part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were found to contain neuropeptide Y, agouti-related peptide (AGRP) and GAD. In the ventrolateral part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were shown to contain pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. In the LHA, GABA(B)R1 immunoreactivity was present in both melanin-concentrating hormone- and orexin-containing cell populations. In the tuberomammillary nucleus, GABA(B)R1-immunoreactive cell bodies expressed histidine decarboxylase, a marker for histamine-containing neurones. In addition, GAD and AGRP were found to be colocalized in some nerve terminals surrounding GABA(B)R1-immunoreactive cell bodies in the parvocellular part of the PVN. The results may provide a morphological basis for the understanding of how GABA regulates the hypothalamic control of food intake and body weight via GABA(B) receptors.

Expression and distribution of metabotropic GABA receptor subtypes GABABR1 and GABABR2 during rat neocortical development.

To understand the possible contribution of metabotropic gamma-aminobutyric acid receptors (GABABR) in cortical development, we investigated the expression pattern and the cellular and subcellular localization of the GABABR1 and GABABR2 subtypes in the rat neocortex from embryonic day 14 (E14) to adulthood. At the light microscopic level, both GABABR1 and GABABR2 were detected as early as E14. During prenatal development, both subtypes were expressed highly in the cortical plate. Using double immunofluorescence, GABABR1 colocalized with GABABR2 in neurons of the marginal zone and subplate, indicating that these proteins are coexpressed and could be forming functional GABABRs during prenatal development in vivo. In contrast, only GABABR1 but not GABABR2 was detected in the tangentially migratory cells in the lower intermediate zone. During postnatal development, immunoreactivity for GABABR1 and GABABR2 was distributed mainly in pyramidal cells. Discrete GABABR1-immunopositive cell bodies of interneurons were present throughout the neocortex. In addition, GABABR1 but not GABABR2 was found in identified Cajal-Retzius cells in layer I. At the electron microscopic level, immunoreactivity for GABABR1 and GABABR2 was found in dendritic spines and dendritic shafts at extrasynaptic and perisynaptic sites throughout postnatal development. We further demonstrated the presynaptic localization of GABABR1 and GABABR2, as well as the association of the receptors with asymmetrical synaptic junctions. These results indicate potentially important roles for the GABABRs in the regulation of migratory processes during corticogenesis and in the modulation of synaptic transmission during early development of cortical circuitry.

Distinct localization of GABAB receptors relative to synaptic sites in the rat cerebellum and ventrobasal thalamus

Metabotropic gamma-aminobutyric acid receptors (GABA(B)Rs) are involved in modulation of synaptic transmission and activity of cerebellar and thalamic neurons. We used subtype-specific antibodies in pre- and postembedding immunohistochemistry combined with three-dimensional reconstruction of labelled profiles and quantification of immunoparticles to reveal the subcellular distribution of pre- and postsynaptic GABA(B)R1a/b and GABA(B)R2 in the rat cerebellum and ventrobasal thalamus. GABA(B)R1a/b and R2 were extensively colocalized in most brain regions including the cerebellum and thalamus. In the cerebellum, immunoreactivity for both subtypes was prevalent in the molecular layer. The most intense immunoreactivity was found in Purkinje cell spines with a high density of immunoparticles at extrasynaptic sites peaking at around 240 nm from glutamatergic synapses between spines and parallel fibre varicosities. This is in contrast to dendrites at sites around GABAergic synapses where sparse and random distribution was found for both subtypes. In addition, more than one-tenth of the synaptic membrane specialization of spine-parallel fibre synapses were labelled at pre- or postsynaptic sites. Weak immunolabelling for both subtypes was also seen in parallel fibres but only rarely in GABAergic axons. In the ventrobasal thalamus, immunolabelling for both receptor subtypes was intense over the dendritic field of thalamocortical cells. Electron microscopy demonstrated an extrasynaptic localization of GABA(B)R1a/b and R2 exclusively in postsynaptic elements. Quantitative analysis further revealed the density of GABA(B)R1a/b around GABAergic synapses was higher than glutamatergic synapses on thalamocortical cell dendrites. The distinct localization of GABA(B)Rs relative to synaptic sites in the cerebellum and ventrobasal thalamus suggests that GABA(B)Rs differentially regulate activity of different neuronal populations.

The gamma-aminobutyric acid receptor B, but not the metabotropic glutamate receptor type-1, associates with lipid rafts in the rat cerebellum.

Recent evidence suggests that specialized microdomains, called lipid rafts, exist within plasma membranes. These domains are enriched in cholesterol and sphingolipids and are resistant to non-ionic detergent-extraction at 4 degrees C. They contain specific populations of membrane proteins, and can change their size and composition in response to cellular signals, resulting in activation of signalling cascades. Here, we demonstrate that both the metabotropic gamma-aminobutyric acid receptor B (GABA(B) receptor) and the metabotropic glutamate receptor-1 from rat cerebellum are insoluble in the non-ionic detergent Triton X-100. However, only the GABA(B) receptor associates with raft fractions isolated from rat brain by sucrose gradient centrifugation. Moreover, increasing the stringency of isolation by decreasing the protein : detergent ratio caused an enrichment of the GABA(B) receptor in raft fractions. In contrast, depletion of cholesterol from cerebellar membranes by either saponin or methyl-beta-cyclodextrin treatment, which solubilize known raft markers, also increased the solubility of the GABA(B) receptor. These properties are all consistent with an association of the GABA(B) receptor with lipid raft microdomains.

GABA(B) receptor autoradiography in hippocampal sclerosis associated with human temporal lobe epilepsy.

1. Metabotropic gamma-aminobutyric acid receptors (GABA(B)) exist both pre- and postsynaptically throughout the brain, mediating the suppression of neurotransmitter release and late inhibitory postsynaptic potentials. Investigation of GABA(B) receptors in rodent models of temporal lobe epilepsy (TLE) suggests that expression or function of these receptors may be altered in the disorder. 2. The aim of the present study was to investigate the expression of GABA(B) receptors in samples of hippocampus surgically resected from patients with hippocampal sclerosis (HS) related intractable TLE, and compare this expression with samples of neurologically normal post-mortem (PM) control hippocampal tissue. Appropriate measures of neuronal loss associated with HS were investigated for comparison with receptor binding data. 3. Receptor autoradiography with [(3)H]-GABA in the presence of isoguvacine, and quantitative densitometric analysis were used to investigate GABA(B) receptor expression (B(max)) and affinity (K(D)) in 11 HS samples and eight controls. A three-dimensional cell counting technique was used to assess neuronal density in both groups. 4. GABA(B) receptor density was significantly reduced in CA1, CA2, CA3, hilus and dentate gyrus, and increased in the subiculum, of HS cases as compared with PM controls. Neuronal loss was significant in all regions measured. When adjusted for neuronal loss, CA1 GABA(B) receptor expression appeared significantly upregulated (P:<0.05). 5. In HS/TLE, GABA(B) receptor expression per remaining neurone appears increased in CA1. This finding, and increased [(3)H]-GABA affinity at CA3 and hilar GABA(B) receptors, suggests altered GABA(B) receptor function may occur in human HS/TLE, possibly as a result of synaptic reorganization.

Neuronal discriminator formed by metabotropic gamma-aminobutyric acid receptors.

Neuronal discriminator formed by metabotropic gamma-aminobutyric acid receptors. J. Neurophysiol. 80: 3365-3368, 1998. Neurotransmitters function in one of two modes, promoting either inhibition or excitation. However, the metabotropic gamma-aminobutyric acid receptor (GABABR) system can switch between these modes. In the presence of a small excitatory stimulus, the GABABR mediates a shunting inhibition that suppresses excitation. However, in the presence of a strong excitatory stimulus, the GABABR potentiates the response. This bipartite action is accomplished by linking the GABABR to two electrogenic mechanisms; one activates an outward current and another reduces an outward current. As a consequence, the GABABR serves as a discriminator that reduces the influence of weak signals while augmenting responses to strong signals. In retinal ganglion cells, this mechanism acts to promote the communication of phasic information.