SLC1A3 encodes EAAT1 (Excitatory Amino Acid Transporter 1, also called GLAST), a sodium-dependent, high-affinity transporter of the acidic amino acids L-glutamate, L-aspartate and D-aspartate. It is a plasma-membrane, multi-pass symporter that co-transports one acidic amino acid with three Na+ and one H+ coupled to the counter-transport of one K+, and in addition carries a thermodynamically uncoupled chloride conductance. EAAT1 assembles as a homotrimer in which each protomer uses an elevator-like transport domain to move substrate across the membrane. It is the predominant glutamate transporter of the cerebellum (Bergmann glia) and is also expressed in retinal Müller glia, the inner ear and some peripheral tissues such as adipocytes. By rapidly clearing synaptically released glutamate from the extracellular space, EAAT1 terminates excitatory signalling and protects neurons from glutamate excitotoxicity. Loss-of-function and dominant-negative variants cause episodic ataxia type 6, with seizures, migraine and alternating hemiplegia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001504 neurotransmitter uptake | TAS PMID:8647279 Human high affinity, Na(+)-dependent L-glutamate/L-aspartate... | ACCEPT | Summary: EAAT1 mediates high-affinity reuptake of the neurotransmitter glutamate from the extracellular/synaptic space, the physiological process that defines the EAAT family. Reason: This is a precise and well-supported description of the gene's physiological role. EAAT1 clears released glutamate from the synaptic cleft to terminate signalling and prevent excitotoxicity. Supporting Evidence: PMID:16116111 the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft PMID:7521911 Reuptake plays an important role in regulating synaptic and extracellular concentrations of glutamate. |
| GO:0005313 L-glutamate transmembrane transporter activity | IBA GO_REF:0000033 | TOO GENERAL | Summary: Phylogenetic (IBA) assertion that EAAT1 is an L-glutamate transmembrane transporter, placed on the SLC1/EAAT node (PANTHER:PTN000238242). The target's own experimental annotation appears in WITH/FROM, which is expected and marks experimental grounding on the target. Reason: The claim is correct, but a more specific molecular function asserted elsewhere in this review, high-affinity L-glutamate transmembrane transporter activity (GO:0005314, ACCEPT), already entails it. The term is true but uninformative relative to the accepted specific activity. Supporting Evidence: PMID:7521911 The affinities of the EAAT subtypes for L-glutamate were similar, with Km determinations varying from 48 to 97 microM in the mammalian cell assay and from 18 to 28 microM in oocytes. |
| GO:0005313 L-glutamate transmembrane transporter activity | IDA PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | TOO GENERAL | Summary: Direct demonstration (expression cloning, radiolabel uptake and voltage clamp) that EAAT1 transports L-glutamate across the membrane. Reason: Correct and experimentally grounded, but entailed by the accepted more-specific term high-affinity L-glutamate transmembrane transporter activity (GO:0005314). TOO_GENERAL judges the term, not this IDA evidence, which is sound. Supporting Evidence: PMID:7521911 The affinities of the EAAT subtypes for L-glutamate were similar, with Km determinations varying from 48 to 97 microM in the mammalian cell assay and from 18 to 28 microM in oocytes. |
| GO:0005313 L-glutamate transmembrane transporter activity | IEA GO_REF:0000120 | TOO GENERAL | Summary: Electronic transfer of L-glutamate transporter activity from the mouse ortholog (P56564). Reason: Correct but entailed by the accepted high-affinity L-glutamate transmembrane transporter activity (GO:0005314). |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | IDA PMID:26690923 Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters... | ACCEPT | Summary: EAAT1 expressed in Xenopus oocytes generates an L-glutamate-induced inward current, the hallmark of high-affinity electrogenic glutamate transport. Reason: This is the canonical, experimentally established core molecular function of EAAT1 - high-affinity (low-micromolar Km) electrogenic L-glutamate uptake. Supporting Evidence: PMID:26690923 The L-glutamate (2 mM)-induced inward current (I Glu) was taken as a measure of glutamate transport. PMID:8123008 expression of a transport activity with a high affinity for glutamate (Km = 78.4 microM) and a dependency on external Na+ |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of high-affinity L-glutamate transporter activity from the mouse ortholog. Reason: Consistent with the experimentally established core activity of EAAT1. |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | IMP PMID:28032905 The amino acid transporter, SLC1A3, is plasma membrane-local... | ACCEPT | Summary: Mutation/expression studies in adipocytes and oocytes confirm EAAT1 high-affinity acidic amino acid transport activity. Reason: Core molecular function, supported by direct functional assays. Supporting Evidence: PMID:28032905 We show that SLC1A3 is localised to the plasma membrane and the major regulator of acidic amino acid uptake in adipocytes. |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | IMP PMID:8123008 Cloning and expression of a human glutamate transporter. | ACCEPT | Summary: Expression of the cloned human transporter in oocytes conferred high-affinity, Na+-dependent glutamate transport. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:8123008 expression of a transport activity with a high affinity for glutamate (Km = 78.4 microM) and a dependency on external Na+ |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | TAS Reactome:R-HSA-210404 | ACCEPT | Summary: Reactome records EAAT1 as a high-affinity glutamate transporter in the astrocytic glutamate uptake pathway. Reason: Consistent with the experimentally established core activity. |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | TAS Reactome:R-HSA-428015 | ACCEPT | Summary: Reactome records EAAT1 as a high-affinity glutamate transporter. Reason: Consistent with the experimentally established core activity. |
| GO:0005314 high-affinity L-glutamate transmembrane transporter activity | TAS Reactome:R-HSA-5625015 | ACCEPT | Summary: Reactome records EAAT1 as a high-affinity glutamate transporter (module also used to model the EA6 defective state). Reason: Consistent with the experimentally established core activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction with TMEM120B from a large-scale human interactome (HuRI) screen. Reason: Bare protein binding (GO:0005515) is uninformative and is removed per the protein-binding policy. Removal does not dispute the reported interaction; it reflects that the term conveys no specific molecular function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction with MGST3 from a large-scale human interactome screen. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction with TMEM128 from a large-scale human interactome screen. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction with BTN2A2 from a large-scale human interactome screen. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Interaction with the PDZ scaffold PDZK1 from the BioPlex proteome-scale network. Reason: Uninformative bare protein binding; removed per the protein-binding policy. Several EAAT1 partners are C-terminal PDZ scaffolds relevant to anchoring/trafficking, but a specific molecular function cannot be asserted from binary-interaction data alone. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with GRID2IP (delphilin) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with MPDZ (MUPP1) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with DLG4 (PSD-95) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with APBA1 (Mint1) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with TJP1 (ZO-1) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with DLG1 (SAP97) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Interaction with IL16 (a PDZ-domain protein) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with DLG2 (PSD-93) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with PDZK1 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with FRMPD2 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with MAGI2 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with NHERF4 (PDZD3) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with LNX2 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with PATJ (INADL) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with LNX1 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with DLG3 (SAP102) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with MAGI1 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with APBA2 (Mint2) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with GRIP2 from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with WHRN (whirlin) from affinity-based fragmentomics. Reason: Uninformative bare protein binding; removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ-motif interaction with GRIP1 from affinity-based fragmentomics; GRIP1 binds the EAAT1 C-terminus and participates in its membrane anchoring. Reason: Uninformative bare protein binding; removed per the protein-binding policy. The PDZ scaffold interactions collectively point to C-terminal anchoring/trafficking but no specific MF term is assertable from binary-interaction data alone. |
| GO:0005886 plasma membrane | EXP PMID:20477940 The position of an arginine residue influences substrate aff... | ACCEPT | Summary: EAAT1 is a plasma-membrane transporter; function was assayed at the cell surface. Reason: The plasma membrane is the established site of EAAT1 action, directly demonstrated by functional and localization studies. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | EXP PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | ACCEPT | Summary: EAAT1 localizes to and functions at the plasma membrane. Reason: Core, directly supported localization for a cell-surface transporter. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that EAAT1 is active at the plasma membrane, consistent with the family and with direct evidence on the target (whose own annotation appears in WITH/FROM). Reason: The plasma-membrane location is correct and is the site where the transport activity occurs. The target's appearance in WITH/FROM marks experimental grounding, not circularity. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of plasma-membrane localization. Reason: Consistent with experimentally established plasma-membrane localization. |
| GO:0005886 plasma membrane | IMP PMID:26690923 Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters... | ACCEPT | Summary: Plasma-membrane localization inferred from functional expression at the oocyte surface. Reason: Core localization, consistent with all other evidence. |
| GO:0005886 plasma membrane | IMP PMID:28032905 The amino acid transporter, SLC1A3, is plasma membrane-local... | ACCEPT | Summary: EAAT1 was shown to be plasma-membrane-localized in adipocytes. Reason: Direct localization evidence. Supporting Evidence: PMID:28032905 We show that SLC1A3 is localised to the plasma membrane and the major regulator of acidic amino acid uptake in adipocytes. |
| GO:0005886 plasma membrane | IMP PMID:8123008 Cloning and expression of a human glutamate transporter. | ACCEPT | Summary: Functional expression at the oocyte surface implies plasma-membrane localization. Reason: Consistent with the established core localization. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of plasma-membrane localization from an ortholog. Reason: Consistent with experimentally established plasma-membrane localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-210404 | ACCEPT | Summary: Reactome places EAAT1 at the plasma membrane in the astrocytic glutamate uptake pathway. Reason: Consistent with the established core localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-428015 | ACCEPT | Summary: Reactome places EAAT1 at the plasma membrane. Reason: Consistent with the established core localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5625015 | ACCEPT | Summary: Reactome places EAAT1 at the plasma membrane. Reason: Consistent with the established core localization. |
| GO:0006836 neurotransmitter transport | IEA GO_REF:0000117 | TOO GENERAL | Summary: Electronic (ARBA) assignment of neurotransmitter transport. Reason: Correct but entailed by the more specific accepted process neurotransmitter uptake (GO:0001504); the direction and substrate are known. |
| GO:0006836 neurotransmitter transport | TAS Reactome:R-HSA-210500 | TOO GENERAL | Summary: Reactome places EAAT1 in the glutamate neurotransmitter release/uptake cycle under the general process of neurotransmitter transport. Reason: Correct but entailed by the more specific accepted process neurotransmitter uptake (GO:0001504). |
| GO:0006865 amino acid transport | TAS Reactome:R-HSA-9958863 | TOO GENERAL | Summary: Reactome groups EAAT1 under SLC-mediated amino acid transport. Reason: Correct but entailed by the specific accepted import processes (L-glutamate/L-aspartate/ D-aspartate import across plasma membrane). |
| GO:0007268 chemical synaptic transmission | TAS PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | MARK AS OVER ANNOTATED | Summary: EAAT1 reuptake shapes glutamatergic signalling by clearing released glutamate. Reason: EAAT1 does not perform synaptic transmission (release and receptor activation); it terminates/regulates it by removing glutamate from the cleft. The precise role is captured by neurotransmitter uptake (GO:0001504). This broader process term over-states EAAT1's participation. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt in the rapid removal of released glutamate from the synaptic cleft |
| GO:0009925 basal plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of basal/basolateral plasma-membrane localization, relevant in polarized epithelia (e.g. retina). Reason: A specific plasma-membrane subdomain consistent with EAAT1 distribution in polarized cells, but peripheral to the core synaptic/glial glutamate-clearance function. |
| GO:0009986 cell surface | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of cell-surface localization from the mouse ortholog. Reason: Consistent with the plasma-membrane localization of EAAT1 (external face); retained but peripheral relative to the specific plasma-membrane term. |
| GO:0015172 acidic amino acid transmembrane transporter activity | IEA GO_REF:0000107 | TOO GENERAL | Summary: Electronic assignment of acidic amino acid transporter activity (the class covering glutamate and aspartate). Reason: Correct (EAAT1 transports the acidic amino acids glutamate and aspartate) but entailed by the accepted more-specific high-affinity L-glutamate transmembrane transporter activity (GO:0005314) and the accepted aspartate import processes. |
| GO:0015175 neutral L-amino acid transmembrane transporter activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic assertion of neutral L-amino acid transporter activity, seeded largely from the ASCT paralogs of the SLC1 family (e.g. SLC1A4/ASCT1, SLC1A5/ASCT2) present in the WITH/FROM list. Reason: Neutral amino acid transport is the function of the ASCT clade of SLC1, not of the EAAT1 (acidic amino acid transporter) subfamily. EAAT1's characterized substrates are the acidic amino acids L-glutamate, L-aspartate and D-aspartate; neutral amino acids are not substrates. This IBA reflects an over-broad node placement for the EAAT1 lineage. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000238242 SUPPORTS SOURCE BUT NOT TARGET SLC1 family node whose neutral-amino-acid transport function arose in the ASCT (SLC1A4/SLC1A5) clade; it does not transfer to the acidic-amino-acid EAAT1 subfamily. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate |
| GO:0015293 symporter activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro-based assignment of generic symporter activity. Reason: Correct but entailed by the accepted, mechanistically specific glutamate:sodium symporter activity (GO:0015501). |
| GO:0015501 glutamate:sodium symporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that EAAT1 is a glutamate:sodium symporter, consistent with direct biophysical evidence on the target (whose own annotation is in WITH/FROM). Reason: This mechanistically specific molecular function is the core activity of EAAT1 - Na+-coupled electrogenic glutamate symport - and is directly supported by functional assays. |
| GO:0015501 glutamate:sodium symporter activity | IDA PMID:20477940 The position of an arginine residue influences substrate aff... | ACCEPT | Summary: Electrophysiology of EAAT1 in oocytes demonstrates Na+-coupled, K+-dependent electrogenic glutamate/aspartate transport. Reason: Direct evidence for the core Na+-coupled symport mechanism. Supporting Evidence: PMID:20477940 The EAATs transport glutamate and aspartate with similar micromolar affinities and this transport is coupled to the movement of Na(+), K(+), and H(+). |
| GO:0015501 glutamate:sodium symporter activity | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) assignment of glutamate:sodium symporter activity. Reason: Consistent with the experimentally established core mechanism. |
| GO:0015501 glutamate:sodium symporter activity | IMP PMID:8123008 Cloning and expression of a human glutamate transporter. | ACCEPT | Summary: Expression of the cloned transporter conferred Na+-dependent glutamate transport. Reason: Direct support for the Na+-coupled symport core activity. Supporting Evidence: PMID:8123008 expression of a transport activity with a high affinity for glutamate (Km = 78.4 microM) and a dependency on external Na+ |
| GO:0015804 neutral amino acid transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Process term logically inferred from the neutral L-amino acid transporter activity annotation (GO:0015175). Reason: Inherited from the over-broad neutral-amino-acid transporter activity annotation. EAAT1 transports acidic, not neutral, amino acids, so this derived process is an over-annotation. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate |
| GO:0015813 L-glutamate transmembrane transport | IDA PMID:26690923 Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters... | TOO GENERAL | Summary: Direct demonstration of L-glutamate transport across the membrane by EAAT1. Reason: Correct and experimentally grounded, but entailed by the accepted more-specific process L-glutamate import across plasma membrane (GO:0098712), which specifies both direction and membrane. Supporting Evidence: PMID:26690923 The L-glutamate (2 mM)-induced inward current (I Glu) was taken as a measure of glutamate transport. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based generic membrane localization. Reason: EAAT1 is specifically a plasma-membrane transporter; the generic membrane term should be refined to plasma membrane (GO:0005886), which the gene already carries with direct evidence. Proposed replacements: plasma membrane |
| GO:0016020 membrane | TAS PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | MODIFY | Summary: Early (ProtInc) generic membrane localization. Reason: Refine to the specific, directly supported plasma membrane (GO:0005886). Proposed replacements: plasma membrane |
| GO:0016595 glutamate binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glutamate (substrate) binding, consistent with the structurally defined substrate-binding site in the transport domain. Reason: Substrate binding is a real, structurally confirmed molecular feature (the aspartate/ glutamate site formed by residues around 363-365, 402, 443-447, 476, 483), but it is a sub-activity of the transport cycle rather than the core function label. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt /ligand="L-aspartate" |
| GO:0016597 amino acid binding | IEA GO_REF:0000107 | TOO GENERAL | Summary: Generic amino acid binding. Reason: Correct but entailed by the more specific glutamate binding (GO:0016595) retained as a non-core sub-activity. |
| GO:0031410 cytoplasmic vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of cytoplasmic-vesicle localization, consistent with trafficking of the transporter to and from the surface. Reason: Plausible trafficking-pathway location but peripheral to the plasma-membrane site of transport activity. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of neuron-projection localization from the mouse ortholog. Reason: EAAT1 is predominantly expressed in glia (Bergmann glia, Müller glia); localization to neuronal/glial processes is plausible in some contexts but peripheral and not the core site. |
| GO:0043005 neuron projection | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of neuron-projection localization. Reason: Peripheral localization term, consistent with distribution in cell processes but not core. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of neuronal-cell-body localization from the mouse ortholog. Reason: Peripheral localization; EAAT1 is chiefly glial and its functional site is the surface membrane. |
| GO:0043025 neuronal cell body | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of neuronal-cell-body localization. Reason: Peripheral localization term, not core. |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Synaptic/perisynaptic localization, where EAAT1 clears released glutamate. Reason: Consistent with EAAT1's role at perisynaptic astroglial membranes; a meaningful location but recorded at the plasma-membrane level as the core site. |
| GO:0048471 perinuclear region of cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of perinuclear localization, consistent with the biosynthetic/trafficking pool. Reason: Plausible trafficking-related location but peripheral to the functional surface pool. |
| GO:0051938 L-glutamate import | IDA PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | TOO GENERAL | Summary: Direct demonstration of L-glutamate import by EAAT1. Reason: Correct but entailed by the accepted more-specific process L-glutamate import across plasma membrane (GO:0098712). Supporting Evidence: PMID:7521911 Reuptake plays an important role in regulating synaptic and extracellular concentrations of glutamate. |
| GO:0070633 transepithelial transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of a role in transepithelial transport, relevant where EAAT1 is expressed in polarized epithelia (e.g. retina). Reason: Plausible in specific polarized tissues but peripheral to the central CNS glutamate- clearance role. |
| GO:0070779 D-aspartate import across plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that EAAT1 imports D-aspartate across the plasma membrane, consistent with its established substrate scope. Reason: D-aspartate is a characterized EAAT1 substrate (a hallmark non-metabolized substrate used experimentally), with a curated catalytic reaction in UniProt. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt mediates the uptake of L-glutamate and also L-aspartate and D-aspartate |
| GO:0070779 D-aspartate import across plasma membrane | IDA PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | ACCEPT | Summary: Direct demonstration of D-aspartate import by EAAT1 in heterologous expression. Reason: D-aspartate transport is directly established (Km ~23-47 µM per UniProt kinetics). |
| GO:0070779 D-aspartate import across plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of D-aspartate import from the mouse ortholog. Reason: Consistent with the established substrate scope. |
| GO:0070779 D-aspartate import across plasma membrane | IMP PMID:28032905 The amino acid transporter, SLC1A3, is plasma membrane-local... | ACCEPT | Summary: Mutation/expression study consistent with D-aspartate (acidic amino acid) import. Reason: Consistent with the established acidic amino acid transport function. |
| GO:0070779 D-aspartate import across plasma membrane | IMP PMID:8123008 Cloning and expression of a human glutamate transporter. | ACCEPT | Summary: Expression of the cloned transporter supports acidic amino acid (including D-aspartate) import. Reason: Consistent with the established substrate scope. |
| GO:0071314 cellular response to cocaine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response-to-cocaine annotation transferred electronically from the mouse ortholog, where cocaine exposure alters GLAST/EAAT1 regulation. Reason: A peripheral, context-specific response (from rodent pharmacology) rather than a core molecular or transport function of the human protein; retained but non-core. |
| GO:0071805 potassium ion transmembrane transport | IDA PMID:20477940 The position of an arginine residue influences substrate aff... | KEEP AS NON CORE | Summary: EAAT1 counter-transports K+ as an obligatory step of the glutamate transport cycle; perturbing the TM8 arginine changes K+ coupling. Reason: K+ counter-transport is a genuine, mechanistically integral part of the transport cycle, directly demonstrated, but it is a component of the symport mechanism rather than an independent core function. Supporting Evidence: PMID:20477940 The EAATs transport glutamate and aspartate with similar micromolar affinities and this transport is coupled to the movement of Na(+), K(+), and H(+). |
| GO:0071944 cell periphery | IEA GO_REF:0000107 | TOO GENERAL | Summary: Electronic assignment of cell-periphery localization. Reason: Correct but entailed by the accepted, more specific plasma membrane (GO:0005886), of which cell periphery is an ancestor. |
| GO:0098657 import into cell | IEA GO_REF:0000117 | TOO GENERAL | Summary: Electronic (ARBA) assignment of generic import into cell. Reason: Correct but entailed by the accepted specific processes (L-glutamate/L-aspartate/ D-aspartate import across plasma membrane). |
| GO:0098712 L-glutamate import across plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion of L-glutamate import across the plasma membrane, consistent with direct evidence on the target (whose own annotation is in WITH/FROM). Reason: This is the precise, core physiological process of EAAT1 - directional glutamate uptake at the plasma membrane. |
| GO:0098712 L-glutamate import across plasma membrane | IDA PMID:26690923 Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters... | ACCEPT | Summary: Direct demonstration of electrogenic L-glutamate uptake at the plasma membrane. Reason: Core physiological process, directly supported. Supporting Evidence: PMID:26690923 The L-glutamate (2 mM)-induced inward current (I Glu) was taken as a measure of glutamate transport. |
| GO:0098712 L-glutamate import across plasma membrane | IMP PMID:28032905 The amino acid transporter, SLC1A3, is plasma membrane-local... | ACCEPT | Summary: Mutation/expression study confirms L-glutamate (acidic amino acid) import. Reason: Core physiological process, experimentally supported. |
| GO:0098712 L-glutamate import across plasma membrane | IMP PMID:8123008 Cloning and expression of a human glutamate transporter. | ACCEPT | Summary: Expression of the cloned transporter confers Na+-dependent L-glutamate import. Reason: Core physiological process, experimentally supported. |
| GO:0098796 membrane protein complex | ISS GO_REF:0000024 | ACCEPT | Summary: EAAT1 functions as a homotrimer, which is a membrane protein complex (each protomer transports substrate independently via an elevator mechanism). Reason: The homotrimeric assembly is directly established by the EAAT1 crystal structure, so the protein is genuinely part of a membrane protein complex. Supporting Evidence: PMID:28424515 The structure of EAAT1cryst shows a symmetric homotrimer in a |
| GO:0140009 L-aspartate import across plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion of L-aspartate import across the plasma membrane, consistent with EAAT1's established substrate scope. Reason: L-aspartate is a characterized high-affinity EAAT1 substrate with a curated catalytic reaction in UniProt. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt mediates the uptake of L-glutamate and also L-aspartate and D-aspartate |
| GO:0140009 L-aspartate import across plasma membrane | IDA PMID:20477940 The position of an arginine residue influences substrate aff... | ACCEPT | Summary: Direct demonstration of L-aspartate transport by EAAT1. Reason: L-aspartate import is directly established (and is central to the electrophysiological assays of the transporter). |
| GO:0140009 L-aspartate import across plasma membrane | IDA PMID:7521911 Functional comparisons of three glutamate transporter subtyp... | ACCEPT | Summary: Direct demonstration of L-aspartate import by EAAT1 in heterologous expression. Reason: L-aspartate transport is directly established (Km ~16 µM in oocytes per UniProt kinetics). |
| GO:0140009 L-aspartate import across plasma membrane | IMP PMID:8123008 Cloning and expression of a human glutamate transporter. | ACCEPT | Summary: Expression of the cloned transporter supports L-aspartate import. Reason: Consistent with the established acidic amino acid transport function. |
| GO:0150104 transport across blood-brain barrier | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity inference of a role in transport across the blood-brain barrier. Reason: EAAT1's function is uptake of extracellular glutamate at astroglial/perisynaptic membranes, not vectorial solute transport across the BBB endothelium. The claim over-states the transporter's role; its established function is synaptic glutamate clearance. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt in the rapid removal of released glutamate from the synaptic cleft |
| GO:0150104 transport across blood-brain barrier | NAS PMID:26590417 Establishment and Dysfunction of the Blood-Brain Barrier. | MARK AS OVER ANNOTATED | Summary: Non-traceable author statement citing a general blood-brain-barrier review. Reason: The cited reference is a broad BBB review that does not establish an EAAT1-specific BBB-transport function. EAAT1's characterized role is glutamate reuptake at glial/synaptic membranes, not transport across the BBB. |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | MARK AS OVER ANNOTATED | Summary: Non-traceable author statement citing a general blood-brain-barrier review. Reason: As above, the cited BBB review does not establish an EAAT1-specific BBB-transport function; over-annotation relative to EAAT1's synaptic glutamate-clearance role. |
| GO:1902476 chloride transmembrane transport | IDA PMID:20477940 The position of an arginine residue influences substrate aff... | KEEP AS NON CORE | Summary: EAAT1 carries a thermodynamically uncoupled Cl- conductance (a glutamate-gated anion channel mode) in addition to the coupled amino acid symport. Reason: This is a genuine, directly demonstrated secondary conductance of the EAAT family (not an error), but it is distinct from and secondary to the core high-affinity glutamate transport function. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt Mediates Cl(-) flux that is not coupled to amino acid transport |
| GO:0005253 monoatomic anion channel activity | IDA PMID:20477940 The position of an arginine residue influences substrate aff... | NEW | Summary: Beyond its coupled amino acid symport, EAAT1 functions as a glutamate-gated anion (chloride) channel, conducting Cl- in a manner thermodynamically uncoupled from substrate transport. Reason: The uncoupled anion conductance is a well-established, distinct molecular function of EAATs that is not captured by any existing molecular-function annotation (only the chloride transmembrane transport process term is present). EAAT1 itself conducts the Cl- current, so it executes this activity. The pore is poorly chloride-selective (permeability SCN- > NO3- > I- > Br- > Cl-), so the broader monoatomic anion channel activity term is more accurate than chloride channel activity. Added as a non-core molecular function. Supporting Evidence: file:human/SLC1A3/SLC1A3-uniprot.txt Mediates Cl(-) flux that is not coupled to amino acid transport |
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Download this section (compressed HTML)Q: EAAT1's C-terminus binds many PDZ-domain scaffolds (GRIP1/2, DLG1-4, MAGI1/2, PATJ, MPDZ, PDZK1). Which of these govern surface delivery, perisynaptic clustering and stability of endogenous EAAT1 in Bergmann and Müller glia, versus being incidental interactome hits?
Q: How do EA6 missense variants (e.g. P290R) partition between loss of transport, dominant- negative suppression of wild-type EAAT1 through trimerization, and altered anion conductance?
Q: What is the physiological significance of the uncoupled chloride conductance of EAAT1 for glial membrane potential and glutamate clearance in vivo?
Experiment: Degron-based acute depletion of EAAT1 in human iPSC-derived astrocytes with electrophysiological measurement of glutamate-uptake currents and the uncoupled anion current, to quantify the two conductance modes in a human cellular context.
Experiment: Structure-guided mutagenesis combined with heterologous expression to separate the coupled transport current from the uncoupled Cl- current and map the determinants of each.
Experiment: Co-expression of EA6 variant and wild-type EAAT1 with single-molecule surface tracking to test whether mutant subunits co-assemble into trimers and suppress wild-type surface delivery.
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