Affinage

SLC6A11

Sodium- and chloride-dependent GABA transporter 3 · UniProt P48066

Length
632 aa
Mass
70.6 kDa
Annotated
2026-04-28
57 papers in source corpus 21 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC6A11 encodes GAT-3, an astrocyte-localized, Na⁺- and Cl⁻-dependent high-affinity GABA transporter (Km ~4 µM) that terminates GABAergic signaling by clearing extracellular GABA, thereby regulating both phasic synaptic inhibition and tonic inhibitory tone across basal ganglia, thalamus, cortex, and hippocampus (PMID:7935337, PMID:8815906, PMID:21410779, PMID:29742425). GAT-3 operates bidirectionally: under depolarized or specific ionic conditions, it reverses to release GABA, contributing non-synaptic ambient GABA that activates tonic GABA_A and GABA_B receptor currents, and its transport activity triggers intracellular Ca²⁺ rises via the reverse-mode Na⁺/Ca²⁺ exchanger, coupling GABA uptake to astrocyte-mediated modulation of excitatory transmission (PMID:24324407, PMID:37325697, PMID:39573851). Membrane expression of GAT-3 is dynamically regulated by neuroinflammation, astrocyte Ca²⁺ (via TRPA1 channels), and glutamatergic signaling, and its C-terminal PDZ-binding motif (THF) is required for polarized membrane targeting (PMID:9748227, PMID:22158513, PMID:27090509, PMID:25700791). Loss-of-function variants and haploinsufficiency of SLC6A11 are linked to genetic generalized epilepsy and seizure susceptibility, and disease-associated downregulation of GAT-3 in thalamic astrocytes after brain injury causally promotes circuit hyperexcitability and seizures (PMID:35857628, PMID:39923323).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 High

    Cloning of human SLC6A11 and functional expression established GAT-3 as a Na⁺/Cl⁻-dependent, high-affinity GABA transporter pharmacologically distinct from GAT-1, resolving its transport mechanism and ion stoichiometry (>1 Na⁺ per cycle, 1 Cl⁻) and identifying (S)-SNAP-5114 as the first selective inhibitor.

    Evidence Stable mammalian cell expression with radiolabeled GABA uptake, ion substitution, and pharmacological profiling

    PMID:7874447 PMID:7935337

    Open questions at the time
    • Exact Na⁺:Cl⁻:GABA stoichiometry not determined at atomic level
    • No structural basis for subtype selectivity of SNAP-5114
  2. 1996 High

    Ultrastructural immunolocalization demonstrated that GAT-3 is exclusively expressed in astrocytic processes—not neurons—in the cerebral cortex, establishing the cellular identity of GAT-3 as a glial transporter positioned to limit GABA spillover beyond the synapse.

    Evidence Pre-embedding and post-embedding immunogold electron microscopy with affinity-purified antibodies in rat cortex

    PMID:8815906

    Open questions at the time
    • Regional variation in glial vs. neuronal expression not comprehensively mapped
    • Mechanism of astrocyte-specific expression not addressed
  3. 1998 High

    The C-terminal THF motif was identified as a PDZ-domain-binding determinant required for apical membrane targeting of GAT-3 in polarized epithelial cells, revealing that protein–protein interactions govern its surface localization.

    Evidence Deletion and chimeric constructs expressed in polarized MDCK cells with immunofluorescence

    PMID:9748227

    Open questions at the time
    • Identity of the PDZ-domain partner protein not determined
    • Relevance of apical sorting mechanism to astrocyte membrane targeting not tested
  4. 2005 High

    Electrophysiological studies in cortex and globus pallidus showed that GAT-3 blockade increases inhibitory synaptic currents and tonic GABA tone, establishing that GAT-3 actively limits ambient GABA levels and shapes both phasic and tonic inhibition in vivo-like circuits.

    Evidence Whole-cell patch-clamp in neocortical and GP slices with SNAP-5114 pharmacology and TTX controls

    PMID:16135550 PMID:21410779

    Open questions at the time
    • Relative contribution of GAT-3 vs. GAT-1 to total GABA clearance varies by region and is incompletely quantified
    • Action-potential-dependent component suggests indirect effects not fully dissected
  5. 2011 High

    TRPA1-mediated resting Ca²⁺ in astrocytes was shown to be required for GAT-3 transport activity, linking astrocyte intracellular Ca²⁺ homeostasis to regulation of extracellular GABA and inhibitory synapse efficacy.

    Evidence Genetically encoded Ca²⁺ indicators, TRPA1/GAT-3 pharmacology, and electrophysiology in hippocampal co-cultures and slices

    PMID:22158513

    Open questions at the time
    • Molecular mechanism by which Ca²⁺ regulates GAT-3 activity (direct binding vs. trafficking vs. phosphorylation) not resolved
  6. 2013 High

    GAT-3 was demonstrated to operate in reverse (GABA-releasing) mode in striatal astrocytes, contributing tonic inhibitory current in output neurons; this reverse transport was lost in Huntington's disease models, directly linking bidirectional GAT-3 function to disease pathophysiology.

    Evidence Whole-cell patch-clamp in striatal slices from wild-type and HD model mice with SNAP-5114 and D-aspartate pharmacology

    PMID:24324407

    Open questions at the time
    • Driving force conditions (membrane potential, ion gradients) favoring reverse mode not quantitatively defined
    • Whether HD-associated loss is due to GAT-3 downregulation or altered astrocyte depolarization not distinguished
  7. 2015 Medium

    Glutamate was shown to reduce GAT-3 surface expression in glial cells via ionotropic glutamate receptor activation, establishing a neuron-to-glia signaling pathway that dynamically regulates GAT-3 membrane levels and GABA clearance capacity.

    Evidence Biotinylation, [³H]GABA uptake, and RT-PCR in avian Müller cells with iGluR antagonists

    PMID:25700791

    Open questions at the time
    • Demonstrated in avian retinal glia; replication in mammalian brain astrocytes needed
    • Trafficking vs. transcriptional mechanisms not fully separated
  8. 2016 Medium

    Neuroinflammation-driven microglial activation was shown to increase GAT-3 membrane expression in cerebellar astrocytes, elevating extracellular GABA and causing motor/cognitive deficits—placing GAT-3 trafficking downstream of neuroinflammatory signaling.

    Evidence Immunohistochemistry, Western blot, microdialysis, and behavioral testing in hyperammonemic rats with sulforaphane rescue

    PMID:27090509

    Open questions at the time
    • Precise signaling cascade from microglial activation to GAT-3 membrane insertion not identified
    • Whether increased membrane GAT-3 reflects forward or reverse transport enhancement not determined
  9. 2018 High

    GAT-3 protein downregulation in the external globus pallidus of dopamine-depleted (Parkinsonian) rodents was shown to elevate ambient GABA and cause persistent tonic inhibition, establishing GAT-3 loss as a mechanism for basal ganglia dysfunction in Parkinson's disease models.

    Evidence Western blot, patch-clamp, SNAP-5114 pharmacology, and rotarod behavioral testing in 6-OHDA-lesioned rodents

    PMID:29742425

    Open questions at the time
    • Mechanism of GAT-3 downregulation after dopamine depletion unknown
    • Whether GAT-3 restoration rescues motor phenotype not tested
  10. 2022 High

    Causal evidence that thalamic GAT-3 downregulation after cortical injury drives seizure susceptibility was obtained: viral GAT-3 overexpression in thalamic astrocytes prevented seizures and restored cortical rhythms, and neuroinflammation alone was sufficient to downregulate GAT-3.

    Evidence Viral GAT-3 overexpression, EEG, seizure threshold testing, and immunohistochemistry in traumatic brain injury mouse models

    PMID:35857628

    Open questions at the time
    • Downstream pathway from thalamic GAT-3 loss to cortical hyperexcitability not molecularly defined
    • Whether human post-traumatic epilepsy involves the same mechanism not established
  11. 2024 Medium

    GAT-3 activity in dentate gyrus astrocytes was shown to trigger intracellular Ca²⁺ elevation via reverse Na⁺/Ca²⁺ exchanger activity, which enhances excitatory transmission through presynaptic GluN2B-NMDARs—revealing a non-canonical astrocyte signaling pathway linking GABA uptake to excitatory synaptic modulation and memory formation.

    Evidence Patch-clamp, optogenetics, Ca²⁺ chelation (BAPTA), and contextual fear conditioning in mice

    PMID:39573851

    Open questions at the time
    • Whether this Ca²⁺ signaling pathway operates in other brain regions not tested
    • Molecular identity of the Na⁺/Ca²⁺ exchanger isoform involved not determined
  12. 2025 Medium

    Haploinsufficiency of SLC6A11 was shown to reduce GABA uptake to a degree comparable to pathogenic SLC6A1 variants, and loss-of-function SLC6A11 variants were identified in epilepsy patients with functional validation, establishing SLC6A11 as a genetic epilepsy gene.

    Evidence [³H]GABA uptake in HEK293T cells for haploinsufficiency and patient variants; EEG and clinical outcomes in 3p- syndrome patients

    PMID:39923323

    Open questions at the time
    • Independent replication of genetic association in large epilepsy cohorts needed
    • Animal model of SLC6A11 haploinsufficiency not yet characterized
  13. 2026 High

    Cryo-EM structures of human GAT-3 in substrate-bound (inward-occluded), inhibitor-bound (inward-open), and apo (inward-open) states provided the first atomic-level view of GABA recognition (including a cation-π interaction with Phe in TM6), ion coordination, and the mechanism of selective inhibition through the intracellular permeation pathway.

    Evidence Cryo-EM structural determination of full-length wild-type human GAT-3 with functional validation

    PMID:41611703

    Open questions at the time
    • Outward-open and outward-occluded conformations not captured
    • Structural basis of reverse transport mode not resolved
    • No structures with physiological lipid environment or PDZ-domain partners

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of reverse (GABA-releasing) transport mode, the identity of PDZ-domain partners mediating astrocyte membrane targeting, the molecular mechanism by which intracellular Ca²⁺ regulates GAT-3 activity, and whether SLC6A11 loss-of-function is independently sufficient to cause human epilepsy.
  • Outward-facing structural states not resolved
  • PDZ-domain partner identity unknown
  • Ca²⁺-dependent regulation mechanism (direct vs. trafficking) unresolved
  • Independent large-scale genetic validation of SLC6A11 in epilepsy pending

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-382551 Transport of small molecules 3 GO:0005215 transporter activity 1
Partners
PMCA4TRPA1

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2026 Cryo-EM structures of full-length wild-type human GAT3 (hGAT3) were solved in three states: bound to a selective inhibitor (inward-open conformation), bound to substrate GABA (inward-occluded conformation), and in substrate-free state (inward-open). The GABA-bound structure revealed ion coordination, substrate recognition network, and a cation-π interaction between GABA's γ-amino group and a phenylalanine residue in transmembrane helix 6. The inhibitor binds within the intracellular permeation pathway between transmembrane helices 1, 2, 3, 6, 7, and 8, revealing the molecular basis of selective inhibition. Cryo-electron microscopy structural determination with functional validation Nature communications High 41611703
1994 Stable expression of GAT-3 in LLC-PK1 cells demonstrated that GAT-3 transports GABA with Km ~4 µM and Vmax ~1.25×10⁻¹⁶ mol/cell/min in a Na⁺- and Cl⁻-dependent manner. The Na⁺ dependence showed a Hill coefficient of 1.65 (suggesting >1 Na⁺ per transport cycle), while Cl⁻ dependence was hyperbolic (Hill ~1.05, Km ~78 mM). β-Alanine is both an inhibitor (Ki ~34 µM) and a substrate (Km ~29 µM) at the same or similar binding site as GABA. Neuronal GABA transport inhibitors (tiagabine, Cl-966, etc.) are weak inhibitors of GAT-3. Stable mammalian cell expression, radiolabeled GABA uptake assay, kinetic analysis, ion substitution experiments Molecular pharmacology High 7935337
1994 Cloning and expression of the human homologue of GAT-3 (SLC6A11) identified (S)-SNAP-5114 as a selective inhibitor with IC50 of 5 µM at GAT-3, 21 µM at GAT-2, and ≥100 µM at GAT-1 and BGT-1, establishing pharmacological distinguishability of GAT-3 from other GABA transporter subtypes. Molecular cloning, heterologous expression, pharmacological inhibition assay Receptors & channels High 7874447
1998 Sorting determinants for GAT-3 apical localization in polarized MDCK epithelial cells reside in its C-terminal cytoplasmic tail. Deletion of the final 32 amino acids mislocalized GAT-3 to both surfaces; removal of the terminal three amino acids (THF motif) similarly disrupted apical sorting. The THF motif resembles PDZ-domain-binding motifs, suggesting that apical localization requires a PDZ-mediated protein–protein interaction. A 22-amino-acid sequence at the C-terminus of GAT-2 directed basolateral localization and could redirect GAT-3 to the basolateral surface when appended to GAT-3. Deletion constructs, chimeric transporter expression in MDCK cells, immunofluorescence localization The Journal of biological chemistry High 9748227
2011 In rat hippocampal astrocyte–neuron co-cultures and brain slices, TRPA1 channel-mediated Ca²⁺ influx in astrocytes maintains resting Ca²⁺ levels that regulate GABA transport by GAT-3. Decreasing astrocyte resting Ca²⁺ by blocking TRPA1 reduced GAT-3-mediated GABA transport, elevating extracellular GABA and reducing interneuron inhibitory synapse efficacy. Genetically encoded Ca²⁺ indicator (Lck-GCaMP3), pharmacological blockade of TRPA1 and GAT-3, electrophysiological recording of inhibitory synaptic currents in brain slices Nature neuroscience High 22158513
1996 Immunocytochemistry with electron microscopy localized GAT-3 immunoreactivity exclusively to astrocytic processes in the rat cerebral cortex neuropil. GAT-3-positive astrocytic processes were found adjacent to axon terminals with both symmetric and asymmetric specializations, including non-GABAergic synapses, suggesting that glial GABA uptake limits the spread of GABA beyond the synapse and regulates overall GABA levels in the neuropil. Immunocytochemistry with affinity-purified antibodies, electron microscopy, pre-embedding and post-embedding immunogold labeling The Journal of neuroscience High 8815906
2018 In dopamine-depleted (Parkinsonian) rodent models, GAT-3 protein is downregulated in the external globus pallidus (GP) while GAT-1 remains normal, causing accumulation of extracellular GABA and persistent GABAergic tonic inhibition in GP neurons. Pharmacological blockade of GAT-3 in control animals altered motor coordination in vivo, demonstrating that GAT-3 normally prevents accumulation of ambient GABA in the GP. Western blot for GAT-3/GAT-1 protein levels, whole-cell patch-clamp recording in GP slices, SNAP-5114 pharmacology, in vivo rotarod motor coordination testing Cell reports High 29742425
2022 Down-regulation of GAT-3 in thalamic astrocytes after cortical injury mediates circuit hyperexcitability and seizure risk. Viral enhancement of GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical rhythms, and protected against chemoconvulsant-induced seizures and mortality in a traumatic brain injury mouse model. Thalamic inflammation alone (without cortical injury) was sufficient to down-regulate GAT-3 and phenocopy the neurological deficits. Mouse models of cortical injury, viral vector-mediated GAT-3 overexpression, EEG recording, seizure threshold testing, immunohistochemistry Science translational medicine High 35857628
2013 In wild-type mouse striatal slices, GAT-3 operates in a GABA-releasing (reverse transport) mode when astrocytes are depolarized, contributing to non-synaptic tonic inhibitory current (I_Tonic(GABA)) in striatal output neurons. In Huntington's disease mouse models (Z_Q175_KI, R6/2), this GAT-3-mediated GABA release is lost, reducing tonic inhibition. Glutamate transporter substrate D-aspartate restored non-synaptic GABA release in HD slices, suggesting that astrocyte membrane potential regulates GAT-3 transport direction. Whole-cell patch-clamp in acute striatal slices, SNAP-5114 pharmacology, D-aspartate application, HD mouse models Frontiers in neural circuits High 24324407
2011 In the rat globus pallidus, GAT-3 is localized almost exclusively to glial processes (not in GABAergic terminals or axons), as shown by electron microscopy. Pharmacological blockade with SNAP-5114 increased the amplitude and prolonged the decay time of evoked IPSCs, and increased spontaneous IPSC frequency/amplitude in an action-potential-dependent manner. High concentrations of both GAT-1 and GAT-3 blockers together induced significant GABA_A receptor-mediated tonic currents, indicating complementary roles for the two transporters. Electron microscopy immunolocalization, whole-cell patch-clamp in GP slices, SKF 89976A and SNAP-5114 pharmacology The European journal of neuroscience High 21410779
2005 Pharmacological blockade of GAT-3 with SNAP-5114 in rat neocortical slices reversibly increased the amplitude of evoked GABA_A receptor-mediated responses and increased frequency and amplitude of spontaneous IPSCs in an action-potential-dependent manner, suggesting that GAT-3 normally limits inhibitory interneuron excitability, possibly through carrier-mediated (reverse) GABA release. In vitro neocortical slice preparation, whole-cell patch-clamp, SNAP-5114 pharmacology, TTX control experiments Journal of neurophysiology Medium 16135550
2016 Neuroinflammation in hyperammonemic rats increases membrane expression of GAT-3 in activated cerebellar astrocytes, elevating extracellular GABA and causing motor incoordination and learning impairment. Sulforaphane treatment promoted M2 microglial polarization, deactivated astrocytes, and normalized GAT-3 membrane expression, extracellular GABA levels, and behavioral outcomes, placing GAT-3 membrane trafficking downstream of microglial activation in the neuroinflammation–GABAergic tone pathway. Immunohistochemistry, Western blot for membrane GAT-3 expression, microdialysis for extracellular GABA, behavioral testing (Y-maze, beam walking), sulforaphane pharmacology in hyperammonemic rats Journal of neuroinflammation Medium 27090509
2017 GAT-3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke in mice. Administration of the GAT-3 substrate L-isoserine directly into the infarct increased GAT-3 expression in peri-infarct regions and significantly improved motor recovery in a concentration-dependent manner without affecting infarct volume, suggesting that GAT-3 substrates can upregulate GAT-3 surface expression and that impaired GAT-3 function contributes to stroke-induced tonic inhibition impairing recovery. Photothrombotic stroke mouse model, Western blot for GAT-3 protein, L-isoserine intraparenchymal administration, grid-walking and cylinder behavioral assays Journal of cerebral blood flow and metabolism Medium 29160736
2021 In the ventral pallidum, GAT-3 is upregulated in astrocytes during extinction of heroin seeking. Knockdown of GAT-3 using vivo-morpholino restored heroin seeking in the extinguished context and disrupted extinction, demonstrating that astrocytic GAT-3 upregulation is necessary for extinction of cued heroin seeking. Additionally, knockdown of the actin-binding protein ezrin (reducing astrocyte synaptic proximity) also disrupted extinction, indicating that both GAT-3 expression and astrocyte proximity to D1-MSN terminals are required for extinction-related suppression of drug seeking. Vivo-morpholino knockdown of GAT-3, confocal microscopy with membrane-bound fluorescent tag, conditioned place preference/extinction behavioral paradigm in rats Molecular psychiatry Medium 34642457
2015 Screening of small-molecule libraries against human GAT3 (hGAT3) identified isatin derivatives as a novel class of hGAT3 inhibitors. SAR analysis yielded compounds with >30-fold selectivity for hGAT3 over hGAT1/hGAT2/hBGT1 with low micromolar IC50s. Compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) exhibited noncompetitive inhibition, indicating a binding site distinct from the GABA substrate site, supported by molecular modeling. [³H]GABA uptake assay in hGAT3-expressing cell line, SAR analysis, kinetic inhibition mode analysis, molecular modeling ACS chemical neuroscience Medium 26154082
2003 Following transient focal ischemia in rats, GAT-3 immunoreactivity was reduced in the perilesional cortex and GAT-3 was ectopically expressed in NeuN-positive pyramidal neurons (which do not normally express it). Immunoblotting showed total GAT-3 protein levels were not significantly changed. GAT-3-positive neurons co-expressed HSP70 and were TUNEL-negative, suggesting the neuronal expression is a stress response not associated with cell death. Middle cerebral artery occlusion rat model, immunocytochemistry, NeuN co-labeling, TUNEL assay, HSP70 co-labeling, Western blot Neurobiology of disease Medium 13678673
2024 In the dentate gyrus, activation of astrocytic GAT-3 triggers an increase in intracellular Ca²⁺ via reverse Na⁺/Ca²⁺ exchanger activity. This Ca²⁺ rise enhances excitatory synaptic transmission via presynaptic GluN2B-containing NMDARs. Inhibiting GAT-3 blocked the GABA-induced astrocytic Ca²⁺ elevation and subsequent synaptic enhancement. Endogenous GABA released by interneurons modulates synaptic transmission through GAT-3. In vivo GAT-3 inhibition impaired contextual fear memory formation. Whole-cell patch-clamp, optogenetics, immunohistochemistry, Ca²⁺ chelator (BAPTA) infusion, behavioral fear conditioning assay Glia Medium 39573851
2015 In avian Müller cells, glutamate reduces GAT-3-mediated GABA uptake by ~50% via activation of ionotropic glutamate receptors, decreasing GAT-3 plasma membrane levels as shown by biotinylation experiments. GAT-1 and GAT-3 mRNAs were also reduced by glutamate. Conditioned medium from retinal neurons produced a similar effect preventable by glutamate receptor antagonists (MK-801 + CNQX), indicating neuron-to-glia signaling regulates GAT-3 surface expression. [³H]GABA uptake assay, cell-surface biotinylation, RT-PCR for GAT mRNAs, glutamate receptor pharmacology in cultured avian Müller cells Neurochemistry international Medium 25700791
2025 Haploinsufficiency of SLC6A11 (one allele deleted) reduces GAT-3 protein expression and GABA uptake in HEK293T cells to a degree comparable to known pathogenic SLC6A1 missense variants. Treatment with 4-phenylbutyrate (PBA) partially restored GABA uptake in haploinsufficient cells. In pediatric patients with 3p- syndrome carrying SLC6A1/SLC6A11 co-deletions, PBA treatment reduced epileptiform EEG discharges and improved motor function. [³H]GABA uptake assay, Western blot in HEK293T cells, EEG recordings and neurodevelopmental assessment in human patients Epilepsy research Medium 39923323
2023 In developing GAD67-GFP haplodeficient mice (reduced neuronal GABA), blockade of GAT-3 reproduced the effects of GABA_B receptor blockade (CGP55845) on mEPSC frequency and membrane potential, indicating that GAT-3 operates in reverse (releasing) mode in developing astrocytes to provide ambient GABA for tonic GABA_B receptor activation. This tonic GABA_B activation restricts neuronal network excitability to compensate for reduced neuronal GABA synthesis. Whole-cell patch-clamp (mIPSC, mEPSC recording), multi-electrode array (MEA) network activity recording, pharmacological blockade with CGP55845 and SNAP-5114 in acute cortical slices of GAD67-GFP KI mice Frontiers in synaptic neuroscience Medium 37325697
2025 Missense variants and loss-of-function variants in SLC6A11 identified in patients with genetic generalized epilepsy (GGE) showed reduced GAT-3 GABA uptake activity when functionally validated, linking reduced GAT-3 transport function to epilepsy severity. GABA uptake functional assay for SLC6A11 variants identified by sequencing in epilepsy cohort bioRxivpreprint Medium
2024 Proteochemometric modeling of GAT1/BGT1/GAT2/GAT3 inhibitor datasets identified residue Q299 in GAT3 (corresponding to Leu300/Q299/L294/L314 across subtypes) as a key determinant of GAT3 subtype selectivity for inhibitor binding. Proteochemometric modeling (partial least squares and random forest), compiled bioactivity dataset of 323 compounds across four GAT subtypes bioRxivpreprint Low
2025 In C6 glioma cells, GAT-3 interacts with PMCA4 within lipid raft microdomains and with calmodulin. GABA stimulation through GAT-3 modulates local Ca²⁺ dynamics in lipid rafts; long-term GABA stimulation disrupts the PMCA4/GAT-3 complex, overloads lipid rafts with Ca²⁺, and promotes CaMKII-dependent CREB phosphorylation at Ser133. Ca²⁺ chelation in rafts abolished GABA-stimulated Ca²⁺ rises and restored migratory potential, demonstrating a GAT-3-dependent Ca²⁺ compartmentalization mechanism regulating glioma invasiveness. Co-immunoprecipitation, lipid raft fractionation, Ca²⁺ imaging, PMCA4 knockdown, calmodulin interaction assay, CREB phosphorylation analysis, migration/invasion assays in C6 glioma cells Cell calcium Low 40580687
2024 Multiplexed CRISPR/Cas9 knockout of Gat3 in mouse visual cortex astrocytes altered spontaneous and visually driven neuronal response magnitudes and trial-to-trial variability, and impaired population-level stimulus encoding, demonstrating that astrocytic GAT-3 shapes sensory information encoding in visual cortex. CRISPR/Cas9 knockout in adult mouse visual cortex, in vivo two-photon Ca²⁺ imaging of neuronal responses to visual stimuli bioRxivpreprint Medium

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nature neuroscience 369 22158513
1996 GAT-3, a high-affinity GABA plasma membrane transporter, is localized to astrocytic processes, and it is not confined to the vicinity of GABAergic synapses in the cerebral cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 224 8815906
1994 Production of specific antibodies against GABA transporter subtypes (GAT1, GAT2, GAT3) and their application to immunocytochemistry. Brain research. Molecular brain research 115 7854065
1996 Multiple gamma-Aminobutyric acid plasma membrane transporters (GAT-1, GAT-2, GAT-3) in the rat retina. The Journal of comparative neurology 99 8915826
2016 Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia. Journal of neuroinflammation 96 27090509
1994 Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site. Receptors & channels 94 7874447
2013 Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3. Frontiers in neural circuits 85 24324407
1998 Identification of sorting determinants in the C-terminal cytoplasmic tails of the gamma-aminobutyric acid transporters GAT-2 and GAT-3. The Journal of biological chemistry 79 9748227
2011 Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia. Frontiers in systems neuroscience 64 21847373
1996 Neuronal and glial localization of two GABA transporters (GAT1 and GAT3) in the rat cerebellum. Brain research. Molecular brain research 61 8738166
2006 GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Acta neuropathologica 53 16456667
1994 Stable expression of a neuronal gamma-aminobutyric acid transporter, GAT-3, in mammalian cells demonstrates unique pharmacological properties and ion dependence. Molecular pharmacology 52 7935337
2018 GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents. Cell reports 49 29742425
2003 Postnatal development of high-affinity plasma membrane GABA transporters GAT-2 and GAT-3 in the rat cerebral cortex. Brain research. Developmental brain research 49 12694940
2003 Expression of GABA transporters, GAT-1 and GAT-3, in the cerebral cortex and thalamus of the rat during postnatal development. Cell and tissue research 49 12898208
2005 GAT-3 transporters regulate inhibition in the neocortex. Journal of neurophysiology 45 16135550
2001 Increased expression of gamma-aminobutyric acid transporters GAT-1 and GAT-3 in the spinal trigeminal nucleus after facial carrageenan injections. Pain 43 11323124
2022 Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents. Science translational medicine 37 35857628
2006 New highly potent GABA uptake inhibitors selective for GAT-1 and GAT-3 derived from (R)- and (S)-proline and homologous pyrrolidine-2-alkanoic acids. European journal of medicinal chemistry 35 16766089
2004 Changes in GABA transporters in the rat hippocampus after kainate-induced neuronal injury: decrease in GAT-1 and GAT-3 but upregulation of betaine/GABA transporter BGT-1. Journal of neuroscience research 35 15248296
2014 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. American journal of medical genetics. Part A 32 25256099
2011 Differential localization and function of GABA transporters, GAT-1 and GAT-3, in the rat globus pallidus. The European journal of neuroscience 32 21410779
2005 Differential expression of the GABA transporters GAT-1 and GAT-3 in brains of rats, cats, monkeys and humans. Cell and tissue research 32 15821932
2018 Expression of functional inhibitory neurotransmitter transporters GlyT1, GAT-1, and GAT-3 by astrocytes of inferior colliculus and hippocampus. Molecular brain 31 29370841
2015 Identification of the First Highly Subtype-Selective Inhibitor of Human GABA Transporter GAT3. ACS chemical neuroscience 30 26154082
2021 Astrocytes in the ventral pallidum extinguish heroin seeking through GAT-3 upregulation and morphological plasticity at D1-MSN terminals. Molecular psychiatry 28 34642457
2009 Reduced expression of GABA transporter GAT3 in helpless rats, an animal model of depression. Neurochemical research 27 19288275
1998 Developmental expression of gamma-aminobutyric acid transporters (GAT-1 and GAT-3) in the rat cerebellum: evidence for a transient presence of GAT-1 in Purkinje cells. Brain research. Developmental brain research 26 9838150
2021 Baclofen decreases compulsive alcohol drinking in rats characterized by reduced levels of GAT-3 in the central amygdala. Addiction biology 25 33527681
2003 Transient focal ischemia triggers neuronal expression of GAT-3 in the rat perilesional cortex. Neurobiology of disease 25 13678673
1999 Developmental expression of the neurotransmitter transporter GAT3. Journal of neuroscience research 23 10348670
2021 Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease. Neurochemical research 22 33710537
2017 GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 22 29160736
2014 Functional analysis of the inhibitory neurotransmitter transporters GlyT1, GAT-1, and GAT-3 in astrocytes of the lateral superior olive. Glia 21 25103283
2000 A light and electron microscopic study of the GABA transporter GAT-3 in the monkey basal ganglia and brainstem. Journal of neurocytology 21 11283414
2005 Neuronal localization of the GABA transporter GAT-3 in human cerebral cortex: a procedural artifact? Journal of chemical neuroanatomy 20 15923108
1999 Expression of GABA transporter subtypes (GAT1, GAT3) in the adult rabbit retina. Acta ophthalmologica Scandinavica 18 10406141
2015 Functional plasticity of GAT-3 in avian Müller cells is regulated by neurons via a glutamatergic input. Neurochemistry international 17 25700791
2013 Gaba transporter SLC6A11 gene polymorphism associated with tardive dyskinesia. Nordic journal of psychiatry 16 23795861
2020 GAT-1 (rs2697153) and GAT-3 (rs2272400) polymorphisms are associated with febrile seizures and temporal lobe epilepsy. Epileptic disorders : international epilepsy journal with videotape 14 32301730
2011 Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance. Journal of human genetics 10 21776001
1999 Immunoreactivity for multiple GABA transporters (GAT-1, GAT-2, GAT-3) in the gerbil pineal gland. Neuroscience letters 10 10353341
1998 Increased expression of GABA transporters, GAT-1 and GAT-3, in the deafferented superior colliculus of the rat. Brain research 10 9479049
2001 Developmental changes in GABA transporter (GAT1 and GAT3) mRNA expressions in the rat olfactory bulb. Brain research. Developmental brain research 9 11248347
2025 4-Phenylbutyrate restored GABA uptake, mitigated seizures in SLC6A1 and SLC6A11 microdeletions/3p- syndrome: From cellular models to human patients. Epilepsy research 7 39923323
1999 Quantitation of GABA transporter 3 (GAT3) mRNA in rat brain by competitive RT-PCR. Brain research. Brain research protocols 7 10592344
2023 Tonic activation of GABAB receptors via GAT-3 mediated GABA release reduces network activity in the developing somatosensory cortex in GAD67-GFP mice. Frontiers in synaptic neuroscience 6 37325697
1999 Expression of GABA transporter subtypes (GAT1, GAT3) in the developing rabbit retina. Acta ophthalmologica Scandinavica 6 10406142
2024 Astrocytic GAT-3 Regulates Synaptic Transmission and Memory Formation in the Dentate Gyrus. Glia 5 39573851
2012 Development and validation of an LC-ESI-MS/MS quantification method for a potential γ-aminobutyric acid transporter 3 (GAT3) marker and its application in preliminary MS binding assays. Biomedical chromatography : BMC 3 23225341
2024 Manganese- and zinc-coordinated interaction of Schistosoma japonicum glutathione S-transferase with neurotransmitter transporters GlyT1 and GAT3 in vitro. Experimental parasitology 2 38369179
2017 Lack of Association between SLC6A11 Genetic Polymorphisms and Drug Resistant Epilepsy in Chinese Han Population. Clinical laboratory 2 28792706
2026 Structural basis for selective inhibition of human GABA transporter GAT3. Nature communications 0 41611703
2026 Prelimbic cortex to zona incerta pathway mediates recognition memory recovery delay through down-regulating astrocytic GAT-3. iScience 0 41797906
2025 GAT3-dependent regulation of glioma invasiveness via a lipid raft-associated PMCA4 Ca2+ transporter and a downstream CaMKII/CREB signaling - implications for compartmentalized signaling in glioma tumors. Cell calcium 0 40580687
2025 Association of CYP3A4*1B and SLC6A11 Genetic Variants with Epilepsy Risk And Antiepileptic Drug Response in an Iraqi Population. Molecular neurobiology 0 41410815
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