id: E7F1V8 gene_symbol: gria1b product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: gria1b (glutamate receptor, ionotropic, AMPA 1b) is one of two zebrafish co-orthologs of vertebrate GRIA1 (GluA1), retained from the teleost-specific genome duplication; its paralog is gria1a. It encodes an AMPA-type ionotropic glutamate receptor subunit that, by homology, forms tetrameric glutamate-gated cation channels at excitatory postsynaptic sites. The ligand-binding residues, channel pore and M2-M3 gating segment are identical to those of gria1a and human GRIA1, but gria1b has evolved faster than gria1a since the duplication, most visibly in its cytoplasmic tail, where it lacks serines matching the mammalian CaMKII/PKC (S831) and PKA (S845) phosphorylation sites. gria1b is expressed in many of the same neuronal populations as gria1a in the developing brain, retina and spinal cord, at lower levels in larvae, with an additional otic vesicle domain and RNA-seq signal in ovary, spleen and gill. No loss-of-function study of gria1b alone has been reported. existing_annotations: - term: id: GO:0004971 label: AMPA glutamate receptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - MGI:MGI:95808 - PANTHER:PTN000438081 - RGD:61862 - RGD:61863 - RGD:621531 - RGD:70958 - UniProtKB:P42261 - UniProtKB:P42263 - UniProtKB:P48058 review: summary: AMPA glutamate receptor activity propagated from the AMPA-receptor node PTN000438081 (donors include human GRIA1 and rodent Gria1-4). action: ACCEPT reason: gria1b is a GRIA1 co-ortholog inside the AMPA-receptor clade and keeps every glutamate-binding residue annotated on human GRIA1, the pore loop and the M2-M3 segment. No zebrafish electrophysiology separates the copies, but there is no sign of loss of the receptor function. gria1b has diverged faster than gria1a and its C-terminal tail has lost the serines that correspond to the mammalian CaMKII/PKC and PKA phosphorylation sites, but the ligand-binding and pore residues are intact, so the channel activity itself is not in doubt. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - AGI_LocusCode:AT1G05200 - AGI_LocusCode:AT1G42540 - AGI_LocusCode:AT4G35290 - FB:FBgn0004620 - FB:FBgn0020429 - FB:FBgn0028422 - FB:FBgn0035604 - FB:FBgn0038837 - FB:FBgn0039927 - FB:FBgn0046113 - FB:FBgn0051201 - FB:FBgn0052704 - FB:FBgn0053513 - MGI:MGI:1933206 - MGI:MGI:2150393 - MGI:MGI:95808 - MGI:MGI:95809 - MGI:MGI:95810 - MGI:MGI:95811 - MGI:MGI:95812 - MGI:MGI:95813 - MGI:MGI:95814 - MGI:MGI:95816 - MGI:MGI:95817 - MGI:MGI:95818 - MGI:MGI:95819 - MGI:MGI:95820 - MGI:MGI:95821 - MGI:MGI:95822 - MGI:MGI:95823 - PANTHER:PTN000437926 - RGD:2732 - RGD:2733 - RGD:2734 - RGD:2735 - RGD:2736 - RGD:2737 - RGD:2738 - RGD:2739 - RGD:2740 - RGD:61862 - RGD:61863 - RGD:621531 - RGD:621704 - RGD:621705 - RGD:68366 - RGD:68368 - RGD:70958 - RGD:71027 - UniProtKB:A0A1L8F5J9 - UniProtKB:A0A1S4GYH6 - UniProtKB:A7XY94 - UniProtKB:B7ZSK1 - UniProtKB:O15399 - UniProtKB:O43424 - UniProtKB:P39086 - UniProtKB:P42261 - UniProtKB:P42262 - UniProtKB:P42263 - UniProtKB:Q05586 - UniProtKB:Q12879 - UniProtKB:Q13002 - UniProtKB:Q13003 - UniProtKB:Q13224 - UniProtKB:Q14957 - UniProtKB:Q8TCU5 - UniProtKB:Q9ULK0 - WB:WBGene00001612 - WB:WBGene00003774 review: summary: Plasma membrane propagated from the ionotropic glutamate receptor family node PTN000437926. action: ACCEPT reason: AMPA receptor subunits are multi-pass plasma-membrane proteins; the transmembrane and pore segments are fully conserved. supported_by: - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0015276 label: ligand-gated monoatomic ion channel activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR001320 - InterPro:IPR019594 review: summary: Ligand-gated monoatomic ion channel activity from InterPro ionotropic glutamate receptor signatures. action: ACCEPT reason: Correct, less specific parent of AMPA glutamate receptor activity. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - ARBA:ARBA00028763 - InterPro:IPR001320 - InterPro:IPR019594 review: summary: Membrane from combined automated annotation (ARBA and InterPro). action: ACCEPT reason: Correct but uninformative; the more specific postsynaptic density membrane and plasma membrane terms are also present. supported_by: - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0022824 label: transmitter-gated monoatomic ion channel activity evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables supporting_entities: - ARBA:ARBA00028000 review: summary: Transmitter-gated monoatomic ion channel activity from an ARBA rule. action: ACCEPT reason: Correct parent of AMPA glutamate receptor activity. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - term: id: GO:0032281 label: AMPA glutamate receptor complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of supporting_entities: - MGI:MGI:95808 - MGI:MGI:95809 - MGI:MGI:95810 - MGI:MGI:95811 - PANTHER:PTN000438081 - RGD:61862 - RGD:61863 - RGD:621531 - RGD:70958 - UniProtKB:P42261 review: summary: AMPA glutamate receptor complex propagated from PTN000438081, seeded by rodent Gria1-4 and human GRIA1. action: ACCEPT reason: GluA subunits function only as tetrameric AMPA receptor complexes, and the zebrafish subunits keep the features that make up the channel. Zebrafish has eight gria genes that can in principle combine. supported_by: - reference_id: PMID:18224707 supporting_text: Whereas mammals have four subunit genes, Gria1-4, zebrafish has retained a duplicated set of eight genes named gria1-4a and b. - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0034220 label: monoatomic ion transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in supporting_entities: - GO:0015276 - GO:0022824 review: summary: Monoatomic ion transmembrane transport inferred from the channel activity terms. action: ACCEPT reason: The receptor is a cation channel, so ion flux across the membrane is what it mediates. General but correct. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - term: id: GO:0035235 label: ionotropic glutamate receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: involved_in supporting_entities: - GO:0004971 review: summary: Ionotropic glutamate receptor signaling pathway inferred from AMPA glutamate receptor activity. action: ACCEPT reason: Follows directly from the receptor activity. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - term: id: GO:0035249 label: synaptic transmission, glutamatergic evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0004620 - FB:FBgn0020429 - FB:FBgn0039916 - FB:FBgn0039927 - MGI:MGI:95813 - MGI:MGI:95814 - MGI:MGI:95815 - MGI:MGI:95818 - PANTHER:PTN001826301 - RGD:2740 - WB:WBGene00001612 review: summary: Synaptic transmission, glutamatergic propagated from node PTN001826301. action: ACCEPT reason: AMPA receptors carry most fast excitatory transmission, and the protein features needed for it are conserved. gria1b is expressed in many neuronal populations of the developing brain, retina and spinal cord. supported_by: - reference_id: PMID:18224707 supporting_text: As a general rule, each pair of duplicated gria genes is differentially expressed, indicating subfunctionalization of AMPA receptor subunit expression in the teleost lineage. - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0043197 label: dendritic spine evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:95808 - MGI:MGI:95813 - PANTHER:PTN000438081 - RGD:61862 - RGD:61863 - RGD:621531 - RGD:70958 - UniProtKB:P42261 review: summary: Dendritic spine propagated from PTN000438081, seeded by rodent and human GluA1/GluA2. action: KEEP_AS_NON_CORE reason: The location comes from mammalian synapses. Nothing is known about where either zebrafish GluA1 subunit sits at the subcellular level, and many fish neurons form synapses on dendritic shafts. Kept as plausible but non-core; the postsynaptic density membrane term captures the core location. supported_by: - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0045211 label: postsynaptic membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0219 review: summary: Postsynaptic membrane from the UniProt subcellular location (ARBA). action: ACCEPT reason: AMPA receptors are postsynaptic; consistent with the PSD membrane IBA row. supported_by: - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:0050804 label: modulation of chemical synaptic transmission evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0004620 - FB:FBgn0028422 - FB:FBgn0038837 - FB:FBgn0039927 - MGI:MGI:1933206 - MGI:MGI:2150393 - MGI:MGI:95808 - MGI:MGI:95810 - MGI:MGI:95812 - MGI:MGI:95814 - MGI:MGI:95815 - MGI:MGI:95820 - MGI:MGI:95821 - MGI:MGI:95822 - MGI:MGI:95823 - PANTHER:PTN001826301 - RGD:2732 - RGD:2733 - RGD:2737 - RGD:2738 - RGD:2739 - RGD:2740 - RGD:61862 - RGD:61863 - RGD:621531 - RGD:621704 - RGD:70958 - RGD:71027 - UniProtKB:O43424 - UniProtKB:Q13002 - UniProtKB:Q9ULK0 review: summary: Modulation of chemical synaptic transmission propagated from PTN001826301. action: KEEP_AS_NON_CORE reason: In mammals GluA1 is needed for hippocampal LTP, which is regulated partly through phosphorylation of its C-terminal tail. No plasticity experiment exists for either zebrafish copy. gria1b lacks the serines at the positions of the two mammalian regulatory phosphorylation sites, so this role is less secure for gria1b than for gria1a. supported_by: - reference_id: PMID:10364547 supporting_text: In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. - reference_id: PMID:20716669 supporting_text: Ser831 is a substrate for both CaMKII- and PKC-dependent phosphorylation, whereas Ser845 is a substrate for PKA phosphorylation - term: id: GO:0060078 label: regulation of postsynaptic membrane potential evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: involved_in supporting_entities: - GO:1904315 review: summary: Regulation of postsynaptic membrane potential inferred from GO:1904315. action: ACCEPT reason: Follows from the channel activity at postsynaptic sites. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - term: id: GO:0098839 label: postsynaptic density membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:1933206 - MGI:MGI:95808 - MGI:MGI:95809 - MGI:MGI:95812 - MGI:MGI:95813 - MGI:MGI:95816 - MGI:MGI:95818 - MGI:MGI:95820 - MGI:MGI:95821 - MGI:MGI:95822 - PANTHER:PTN001826301 - RGD:2737 - RGD:2738 - RGD:2740 - RGD:61862 - RGD:61863 - RGD:621531 - RGD:621704 - RGD:621705 - RGD:68368 - RGD:70958 - UniProtKB:O43424 review: summary: Postsynaptic density membrane propagated from PTN001826301. action: ACCEPT reason: The standard location of AMPA receptors at excitatory synapses; the protein features are conserved. supported_by: - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - term: id: GO:1904315 label: transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - MGI:MGI:1933206 - MGI:MGI:95808 - MGI:MGI:95809 - MGI:MGI:95810 - MGI:MGI:95811 - MGI:MGI:95812 - MGI:MGI:95815 - MGI:MGI:95818 - MGI:MGI:95822 - PANTHER:PTN001826301 - RGD:2737 - RGD:2738 - RGD:2740 - RGD:61862 - RGD:621531 - UniProtKB:F7AGW3 - UniProtKB:O43424 review: summary: Transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential, propagated from PTN001826301. action: ACCEPT reason: The core activity of an AMPA receptor subunit at the synapse; ligand-binding and pore residues are conserved. supported_by: - reference_id: PMID:2166337 supporting_text: Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX). - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. core_functions: - description: AMPA-type ionotropic glutamate receptor subunit (GluA1 co-ortholog) that, by homology, forms tetrameric glutamate-gated cation channels in the postsynaptic density membrane of excitatory synapses. Ligand-binding and pore residues are conserved; the cytoplasmic tail has diverged, lacking serines at the positions of the mammalian CaMKII/PKC and PKA regulatory sites. Function not measured. molecular_function: id: GO:1904315 label: transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential directly_involved_in: - id: GO:0035249 label: synaptic transmission, glutamatergic locations: - id: GO:0098839 label: postsynaptic density membrane in_complex: id: GO:0032281 label: AMPA glutamate receptor complex supported_by: - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Both copies keep the six glutamate-binding residues, the pore loop and M2-M3 segment, and both palmitoylation cysteines of human GRIA1. - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: gria1b has changed significantly faster than gria1a since the duplication (86 vs 34 unique changes relative to gar). - reference_id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md supporting_text: Most in situ domains are shared; telencephalon, dorsal thalamus, rhombomeres, spinal cord and retinal ganglion cells are recorded for gria1a only and otic vesicle for gria1b only. - reference_id: PMID:20716669 supporting_text: Native GluA1 subunits undergo regulated phosphorylation at two sites (Ser831 and Ser845) in their C-terminal tails references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:2166337 title: A family of AMPA-selective glutamate receptors. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only; cloning and functional expression of rat GluR-A to -D (GluA1-4) as AMPA-selective glutamate-gated cation channels. Background for the molecular function. - id: PMID:10364547 title: Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract only; mouse GluR-A (GluA1) knockout lacks CA1 LTP. Background for the plasticity role. - id: PMID:20716669 title: 'Glutamate receptor ion channels: structure, regulation, and function.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full-text review; GluA1 C-terminal phosphorylation sites Ser831 (CaMKII/PKC) and Ser845 (PKA). - id: PMID:18224707 title: Expression of the eight AMPA receptor subunit genes in the developing central nervous system and sensory organs of zebrafish. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only in cache; in situ survey of all eight zebrafish gria genes at 24-72 hpf. Copy-level domains taken from ZFIN's curation of this paper (gria1a-bioinformatics/output.txt). - id: PMID:16887104 title: 'Embryonic expression of zebrafish AMPA receptor genes: zygotic gria2alpha expression initiates at the midblastula transition.' findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract only; RT-PCR of all eight zebrafish AMPAR genes; maternal transcripts. - id: PMID:30929901 title: Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; gria1 mutants (both copies mutated) have a pallium brain-activity phenotype; gria1a in situ in forebrain; the copy responsible is not stated in the text. - id: file:DANRE/gria1a/gria1a-bioinformatics/RESULTS.md title: gria1a / gria1b protein, expression and synteny comparison reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Local pair analysis directly supports AMPA-receptor ligand-binding, pore, and palmitoylation-site retention in both gria1 paralogs, while separating gria1b C-terminal divergence and expression differences from the conserved ion-channel core. findings: [] suggested_questions: - question: Is the gria1b cytoplasmic tail still phosphorylated by CaMKII/PKC or PKA at nearby residues, and does its divergence change synaptic delivery or plasticity of receptors containing it? - question: Is gria1b expressed in the inner ear and in non-neural tissues (ovary, spleen, gill) as protein, and does gar GRIA1 share these domains? suggested_experiments: - hypothesis: The diverged gria1b tail makes gria1b-containing receptors insensitive to the CaMKII/PKA regulation that acts on gria1a. description: Express gria1a and gria1b (alone and with gria2) in HEK cells or zebrafish neurons; test phosphorylation with phospho-specific assays and measure single-channel conductance and open probability with and without active CaMKII or PKA. experiment_type: electrophysiology - hypothesis: gria1b has an otic vesicle expression domain absent from gria1a. description: Paralog-specific HCR in situ of gria1a and gria1b in the otic vesicle and inner ear at 24-72 hpf and in adult tissues, with gar GRIA1 as outgroup. experiment_type: expression analysis