Delta-1 glutamate receptor (GluD1), a member of the ionotropic glutamate receptor family that is expressed throughout the central nervous system and concentrated in the postsynaptic membrane and postsynaptic density of both excitatory and inhibitory synapses. GluD1 has the full iGluR architecture - amino-terminal domain, clamshell ligand-binding domain, pore-forming transmembrane region and a long cytoplasmic tail - and assembles as a tetramer, but it does not bind glutamate and does not behave like its AMPA, kainate and NMDA relatives. Its best-established role is as a trans-synaptic organiser and signal transducer: the amino-terminal domain binds the secreted proteins cerebellin-1 and cerebellin-2, which in turn bind presynaptic neurexins carrying the splice-site-4 insert, and the resulting neurexin-cerebellin-GluD1 bridge is transduced through short motifs in the cytoplasmic tail to control how much NMDA and AMPA receptor is present postsynaptically. This transduction does not use the channel: chimeras in which the whole transmembrane region is replaced by an unrelated segment remain fully active. GluD1 also binds GABA in its ligand-binding domain and, again non-ionotropically, drives long-lasting potentiation of GABAergic transmission, and it binds D-serine and glycine. Whether GluD1 additionally acts as a ligand-gated ion channel is disputed. Attempts to reproduce direct gating of wild-type receptors by glycine or D-serine found the same currents in untransfected cells and in receptor-null neurons, yet GluD1 demonstrably carries a cation current in native neurons - tonic, partly G-protein-independent, and augmented by Gq-coupled receptor activation - that sets subthreshold excitability and is inhibited by extracellular protons; a 2026 report further describes acetylcholine-evoked GluD1-dependent currents at striatal cholinergic synapses. Loss of GluD1 in rodents alters social behaviour, behavioural flexibility and anxiety-like behaviour, and the locus is associated with neuropsychiatric disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GluD1 is a multi-pass plasma membrane protein of the neuronal surface, concentrated at the postsynaptic membrane. Reason: Uncontroversial and consistent with UniProt (postsynaptic cell membrane, multi-pass). The postsynaptic membrane (GO:0045211) and postsynaptic density membrane (GO:0098839) annotations carried by this gene are the informative ones. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0050804 modulation of chemical synaptic transmission | IBA GO_REF:0000033 | ACCEPT | Summary: Modulating synaptic transmission - rather than mediating it - is precisely what GluD1 does, at both excitatory and inhibitory synapses. Reason: Independently supported for the target itself: the Nrxn-Cbln-GluD1 complex sets postsynaptic NMDA and AMPA receptor levels, and GABA acting on GluD1 produces long-lasting enhancement of GABAergic currents. This is the correct grain for GluD1, which is a modulator and not a transmitting receptor. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:38060673 GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring |
| GO:0098839 postsynaptic density membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GluD1 is a postsynaptic density protein. Reason: Concordant with the IEA and ISS rows for the same term and with direct localisation data; this is the core location of the receptor. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0043197 dendritic spine | IBA GO_REF:0000033 | ACCEPT | Summary: GluD1 is present in dendritic spines, although in some circuits it is predominantly on dendritic shafts. Reason: Correct but circuit-dependent: in the dorsal striatum GluD1 is preferentially found on dendritic shafts rather than spines, so this term should not be read as the exclusive location. Note that this IBA comes from the same AMPA-receptor node (PANTHER:PTN000438081) as the two AMPA annotations rejected below; it happens to be true of GluD1 for independent reasons. Supporting Evidence: PMID:31945419 striatal GluD1 is preferentially found in dendritic shafts |
| GO:0035249 synaptic transmission, glutamatergic | IBA GO_REF:0000033 | ACCEPT | Summary: GluD1 shapes glutamatergic transmission, but as a regulator of NMDA and AMPA receptor levels rather than as a glutamate-gated receptor itself. Reason: The involvement is real and experimentally demonstrated on the target. It must not be read as implying that GluD1 binds glutamate - it does not. GO:0050804 and GO:0099557 capture the modulatory role more precisely. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:31945419 Conditional deletion of GluD1 from the striatum led to a selective loss of thalamic, but not cortical, terminals, and reduced glutamatergic neurotransmission. |
| GO:1904315 transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential | IBA GO_REF:0000033 | UNDECIDED | Summary: Whether GluD1 is directly gated by a neurotransmitter is unresolved; the strongest recent evidence points to indirect (Gq-coupled or tonic) activation of a real pore, with one 2026 report claiming direct ACh gating. Reason: This is the central contested claim about GluD1 and the evidence is genuinely split, so neither ACCEPT nor REMOVE is honest. AGAINST: a dedicated study with the controls the original glycine/D-serine gating reports lacked found identical currents in naive HEK293 cells and in GluD2-null Purkinje neurons, and concluded that extracellular ligands do not directly gate wild-type GluD; UniProt carries this as an explicit CAUTION on Q9ULK0. The GABA effect that GluD1 does mediate is stated by its discoverers to be non-ionotropic. A 2026 review from the field says GluD1 lacks classical ion channel activity. FOR: a 2026 report describes ACh-evoked, NASPM-sensitive currents in medium spiny neurons that are absent in GluD1 knockouts and rescued by GluD1 re-expression - although those authors themselves hedge ("suggesting potential conductance"), and their ligand-binding evidence is an indirect conformational assay. Separately, GluD1 unquestionably carries current in native neurons, but tonically and/or downstream of Gq-coupled receptors, which is not what "transmitter-gated" means. A further proposal is that the channel is simply silent at room temperature because of a high energetic activation barrier. The phylogenetic node behind this IBA (PANTHER:PTN001826301) spans the whole iGluR family including GRID2, so the node placement is not the problem; whether the delta branch retained direct transmitter gating is the problem. Propagation Review Root cause: UNRESOLVED Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001826301 · PAINT node spanning the ionotropic glutamate receptor family UNRESOLVED Donor list spans AMPA, kainate, NMDA and delta subunits, so the node placement itself is defensible; what is unresolved is whether the delta branch retained direct transmitter gating. UniProtKB:O43424 · GRID2 (human) UNRESOLVED The other delta receptor. Its channel is likewise silent in standard assays and is usually studied through the constitutively open Lurcher mutant. UniProtKB:Q61627 · Grid1 (mouse) UNRESOLVED Source of the Ensembl-Compara IEA and the ISS. Mouse Grid1 carries the same unresolved question, so the transfer does not add independent evidence about gating. Supporting Evidence: PMID:39052831 these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels PMID:41345253 primarily due to its lack of classical ion channel activity PMID:38060673 GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring PMID:42270762 produced current responses in medium spiny neurons (MSNs) that were sensitive to the GluD1-channel blocker NASPM PMID:32234214 GluD1R-channels are constitutively active under basal conditions carrying tonic inward current PMID:37154294 GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus. PMID:41741709 they resembled ion channels structurally but appeared functionally silent in standard room-temperature electrophysiological assays |
| GO:0032281 AMPA glutamate receptor complex | IBA GO_REF:0000033 | REMOVE | Summary: GluD1 is not a subunit of an AMPA receptor complex; this is inherited from a PAINT node whose donors are exclusively AMPA receptor subunits. Reason: GluD1 does not assemble into AMPA receptor complexes. Delta receptors form their own homomeric (and GluD1/GluD2 heteromeric) tetramers and their defining partners are the secreted cerebellins and presynaptic neurexins, not GRIA subunits; the GO definition of this complex requires a glutamate-gated ion channel. The propagation is traceable: every WITH/FROM donor for this term is an AMPA receptor subunit (human GRIA1/GRIA3/GRIA4, mouse Gria1, rat Gria orthologues) and the node is PANTHER:PTN000438081, i.e. the IBD was placed on the AMPA clade. GRID1 belongs to the delta branch, which diverged before the AMPA/kainate/NMDA split, and should not inherit from inside the AMPA clade. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000438081 · PAINT node seeding the AMPA-receptor annotations SUPPORTS SOURCE BUT NOT TARGET Every WITH/FROM donor at this node is an AMPA receptor subunit; no delta-receptor donor is present, so the IBD sits on the AMPA clade rather than on an ancestor shared with GRID1. UniProtKB:P42261 · GRIA1 (human) SUPPORTS SOURCE BUT NOT TARGET Genuine glutamate-gated AMPA receptor subunit; the activity does not transfer to the delta branch, which does not bind glutamate. UniProtKB:P42263 · GRIA3 (human) SUPPORTS SOURCE BUT NOT TARGET UniProtKB:P48058 · GRIA4 (human) SUPPORTS SOURCE BUT NOT TARGET MGI:MGI:95808 · Gria1 (mouse) SUPPORTS SOURCE BUT NOT TARGET Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins |
| GO:0004971 AMPA glutamate receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: GluD1 is not an AMPA receptor and is not gated by glutamate; the term is inherited from an AMPA-clade PAINT node. Reason: The GO definition of this term requires an activity that "exhibits fast gating by glutamate". GluD1 does not bind glutamate at all - UniProt states plainly that it "does not bind glutamate as a primary ligand" - so the term is false regardless of where one stands on the wider channel debate. Same propagation defect as GO:0032281: the donors at PANTHER:PTN000438081 are all AMPA receptor subunits and contain no delta receptor, so the IBD node sits on the AMPA clade and GRID1 is outside it. This annotation is also the upstream cause of the inter-ontology IEA to GO:0035235, which falls with it. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000438081 · PAINT node seeding the AMPA-receptor annotations SUPPORTS SOURCE BUT NOT TARGET Every WITH/FROM donor at this node is an AMPA receptor subunit; no delta-receptor donor is present, so the IBD sits on the AMPA clade rather than on an ancestor shared with GRID1. UniProtKB:P42261 · GRIA1 (human) SUPPORTS SOURCE BUT NOT TARGET Genuine glutamate-gated AMPA receptor subunit; the activity does not transfer to the delta branch, which does not bind glutamate. UniProtKB:P42263 · GRIA3 (human) SUPPORTS SOURCE BUT NOT TARGET UniProtKB:P48058 · GRIA4 (human) SUPPORTS SOURCE BUT NOT TARGET MGI:MGI:95808 · Gria1 (mouse) SUPPORTS SOURCE BUT NOT TARGET Supporting Evidence: PMID:38060673 we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs PMID:39052831 these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: GluD1 does form a real conducting pore in native neurons, and that pore is cation-selective, so the more specific cation channel term is preferable to the generic one. Reason: The generic parent is defensible - GluD1 carries a tonic inward current in dorsal raphe neurons, and the current is augmented by Gq-coupled receptor activity - but it is uninformative. The conductance that has been characterised is a cation conductance (UniProt records Na+ and Ca2+ transport for the delta receptors), so GO:0005261 states what is known. Note this is deliberately NOT a ligand-gated channel claim: see GO:0015276 and GO:1904315 below. Proposed replacements: monoatomic cation channel activity Supporting Evidence: PMID:32234214 GluD1R-channels are constitutively active under basal conditions carrying tonic inward current PMID:37154294 GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus. PMID:41345253 The absence of channel activity in vitro contrasts with in vivo evidence suggesting GluD1 can mediate ion conductance under specific physiological conditions. |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Follows from the conducting pore; true but peripheral to what GluD1 does at the synapse. Reason: The tonic and Gq-augmented GluD1 currents are real, so ion transport is not wrong. It is not the core function: the trans-synaptic organiser role is carried out with the pore bypassed entirely. Supporting Evidence: PMID:32234214 GluD1R-channels are constitutively active under basal conditions carrying tonic inward current PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors |
| GO:0007165 signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: GluD1 really is a signal transduction device, but the bare parent term says nothing; the specific trans-synaptic term is available and already used on this gene. Reason: "Signal transduction" is the least informative possible way to record the best-established thing about GluD1. GO:0099557 names the actual mechanism: presynaptic neurexin-cerebellin binding to the GluD1 ATD is converted, through short cytoplasmic motifs, into changes in postsynaptic receptor content. Proposed replacements: trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission Supporting Evidence: PMID:34135511 Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors |
| GO:0015276 ligand-gated monoatomic ion channel activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Direct ligand gating of the GluD1 channel is the specific claim that has been tested and not supported; this InterPro-derived term asserts it by domain homology alone. Reason: The term is not baseless - GluD1 has an intact iGluR ligand-binding domain, binds D-serine, glycine and GABA, and has a pore that conducts - but the step it asserts, ligand binding opening the channel, is exactly what a dedicated study failed to reproduce once naive HEK293 cells and GluD2-null neurons were used as controls. UniProt flags the same point in a CAUTION. The InterPro signatures (IPR001320, IPR019594) that generate this annotation cannot distinguish a gating-competent iGluR from a delta receptor whose ligand binding is transduced non-ionotropically. Marked as over-annotated rather than removed because the 2026 acetylcholine report, if it holds up, would restore it. Supporting Evidence: PMID:39052831 these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels PMID:41345253 This binding does not trigger ion flux through the receptor but initiates a non-ionotropic signaling cascade that enhances inhibitory synaptic transmission. PMID:42270762 produced current responses in medium spiny neurons (MSNs) that were sensitive to the GluD1-channel blocker NASPM |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Uninformative parent of the postsynaptic membrane annotation this gene already carries. Reason: GluD1 is a multi-pass membrane protein, so the term is true, but its location is known precisely. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0034220 monoatomic ion transmembrane transport | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Downstream inference from the channel activity terms; true but peripheral. Reason: Consistent with the treatment of GO:0005216 and GO:0006811: the pore conducts in native neurons, but ion transport is not the core evolved role of GluD1. Supporting Evidence: PMID:37154294 GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus. |
| GO:0035235 ionotropic glutamate receptor signaling pathway | IEA GO_REF:0000108 | REMOVE | Summary: This pathway requires glutamate binding to the receptor followed by ion flux through it; neither step occurs at GluD1. Reason: An inter-ontology logical inference (GO_REF:0000108) drawn from GO:0004971 AMPA glutamate receptor activity, which is itself a mis-propagation and is removed above. The GO definition is explicit that the pathway is "initiated by glutamate binding to a glutamate receptor ... followed by the movement of ions through a channel in the receptor complex". GluD1 does not bind glutamate, so the premise fails and the inference falls with its source. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: GO:0004971 · AMPA glutamate receptor activity (the inference source) SOURCE BAD The source MF annotation is itself a mis-propagation from an AMPA-receptor PAINT node and is removed in this review. Supporting Evidence: PMID:38060673 we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs PMID:39052831 these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: GluD1 does receive extracellular ligands and transduce them, but as a neurotransmitter receptor - the generic parent understates what is known. Reason: GluD1 binds GABA in its ligand-binding domain and transduces it into a lasting change in synaptic strength, and it also binds D-serine and glycine (and, in a 2026 report, acetylcholine). GO:0030594 neurotransmitter receptor activity is the accurate grain and is the parent of the GABA receptor activity term already carried with IDA evidence. It deliberately does not commit to a channel mechanism. Proposed replacements: neurotransmitter receptor activity Supporting Evidence: PMID:38060673 we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs PMID:38060673 The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors. |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000120 | ACCEPT | Summary: GluD1 is a postsynaptic membrane protein; this is among the least contested facts about it. Reason: Directly supported and concordant with the IDA row for the same term. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0048167 regulation of synaptic plasticity | IEA GO_REF:0000117 | ACCEPT | Summary: Regulating plasticity, at both excitatory and inhibitory synapses, is one of the best-supported roles of GluD1. Reason: Supported by mechanism-level work on the target: GABA acting on GluD1 drives long-lasting enhancement of inhibitory transmission, and neurexin-cerebellin signals through GluD1 set NMDA and AMPA receptor levels. An ARBA-generated term that happens to land on solid ground. Supporting Evidence: PMID:38060673 GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:39052831 The transsynaptic triad of Nrxn-Cbln-GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. |
| GO:0060078 regulation of postsynaptic membrane potential | IEA GO_REF:0000117 | ACCEPT | Summary: GluD1 current sets subthreshold excitability in the neurons where it has been recorded, but this is a secondary role. Reason: Directly demonstrated where it has been looked for: blocking GluD1 hyperpolarises dorsal raphe neurons by around 7 mV at subthreshold potentials and reduces excitability, and the current is augmented by Gq-coupled receptor activation. Accepted as the biological process served by the cation-channel activity listed in core_functions, while noting that this is the secondary of the two GluD1 activities: it is circuit-restricted, it has been characterised in only a handful of nuclei, and it is mechanistically separable from the trans-synaptic organiser function, which proceeds with the pore bypassed entirely. Supporting Evidence: PMID:37154294 GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus. PMID:32234214 GluD1R-channels are constitutively active under basal conditions carrying tonic inward current |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Uninformative term, and the only recorded partner is haemoglobin beta from a proteome-scale screen. Reason: 'Bare protein binding carries no functional information and is deprecated by this project. The specific problem here is the partner: both IPI rows come from large-scale affinity-purification interactome screens and both name UniProtKB:P68871, haemoglobin subunit beta, which is a classic affinity-purification contaminant and not a credible partner for a postsynaptic receptor. The interactions that matter for GluD1 - cerebellin-1/2 through the amino-terminal domain, and presynaptic neurexins through cerebellin - are captured by the trans-synaptic protein complex annotation instead.'. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative term, and the only recorded partner is haemoglobin beta from a proteome-scale screen. Reason: 'Bare protein binding carries no functional information and is deprecated by this project. The specific problem here is the partner: both IPI rows come from large-scale affinity-purification interactome screens and both name UniProtKB:P68871, haemoglobin subunit beta, which is a classic affinity-purification contaminant and not a credible partner for a postsynaptic receptor. The interactions that matter for GluD1 - cerebellin-1/2 through the amino-terminal domain, and presynaptic neurexins through cerebellin - are captured by the trans-synaptic protein complex annotation instead.'. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins |
| GO:0030545 signaling receptor regulator activity | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 regulates the levels and activity of other postsynaptic receptors as part of the trans-synaptic complex; this is its best-supported molecular role. Reason: Of everything GOA asserts about the molecular function of GluD1, this is the one that best matches the experimental picture. Within the neurexin-cerebellin-GluD1 trans-synaptic complex, GluD1 regulates the abundance and activity of other postsynaptic receptors (NMDA and AMPA receptors), and it does so through its cytoplasmic tail rather than through its pore - chimeras in which the entire transmembrane/channel region is replaced by an unrelated transmembrane segment retain full activity. The contributes_to qualifier is appropriate, since the regulation requires the assembled trans-synaptic complex. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors PMID:34135511 Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture |
| GO:0035176 social behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Behavioural consequence of GluD1 loss in rodents; real but distal to the molecular function. Reason: Supported by knockout phenotypes in the mouse orthologue and consistent with the human genetics of the locus, but this is an organism-level consequence several steps removed from the molecular activity, and it is not specific: GluD1 loss affects behavioural flexibility, anxiety-like behaviour and compulsive behaviours as well. Kept as contextual, not core. Supporting Evidence: PMID:31945419 selective ablation of GluD1 from the dorsal striatum impairs behavioral flexibility in a water T-maze task PMID:32234214 loss of dorsal raphe GluD1R-channels produces an anxiogenic phenotype |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GluD1 self-associates: like other iGluR-family members it assembles into homomeric oligomers. Reason: Correct - UniProt records a GluD1 homodimer on the basis of the structural work in PMID:38060673, and the functional receptor is a homotetramer - but oligomerisation is a structural prerequisite rather than a function in its own right. Supporting Evidence: PMID:38060673 we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs |
| GO:0045202 synapse | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 acts at synapses; the more specific synapse-type and postsynaptic-membrane annotations are the informative ones. Reason: Uncontested. Retained as the general parent of the glutamatergic-, GABAergic- and cholinergic-synapse localisations. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0098820 trans-synaptic protein complex | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 is the postsynaptic component of the neurexin-cerebellin-GluD trans-synaptic complex. Reason: This is the defining assembly for GluD1: the amino-terminal domain binds secreted cerebellin-1/2, which in turn bind presynaptic neurexins bearing the splice-site-4 insert, bridging the cleft. Recorded with part_of, which is correct. This complex, not the AMPA receptor complex, is the complex GluD1 belongs to. Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins PMID:39052831 The transsynaptic triad of Nrxn-Cbln-GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 is a postsynaptic density protein. Reason: Concordant with the IBA and ISS rows for the same term; core location. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 is present at, and regulates, excitatory synapses. Reason: Directly demonstrated on the target: neurexin-cerebellin signalling through GluD1 controls NMDA and AMPA receptor levels at hippocampal excitatory synapses, and GluD1 organises glutamatergic presynaptic terminals in co-culture. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:22138648 GluD1 induced presynaptic differentiation of not only glutamatergic presynaptic terminals but also GABAergic ones |
| GO:0098982 GABA-ergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 is genuinely present at inhibitory synapses - this is not a mis-mapping despite the gene name. Reason: One of the two localisations that make GluD1 unusual, and it is well supported: GluD1 induces GABAergic as well as glutamatergic presynaptic differentiation, it binds GABA, and GluD1 activation potentiates GABAergic transmission in adult hippocampus. Flagged explicitly because, taken together with the glutamatergic-synapse and cholinergic-synapse data, it is what makes the single-transmitter molecular-function annotations on this gene mutually contradictory. Supporting Evidence: PMID:22138648 GluD1 induced presynaptic differentiation of not only glutamatergic presynaptic terminals but also GABAergic ones PMID:38060673 GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring PMID:38060673 The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors. |
| GO:0099072 regulation of postsynaptic membrane neurotransmitter receptor levels | IEA GO_REF:0000107 | ACCEPT | Summary: Controlling how much NMDA and AMPA receptor sits in the postsynaptic membrane is the measured output of GluD1 signalling. Reason: Directly demonstrated, with the mechanism dissected: distinct presynaptic neurexin-cerebellin complexes act through GluD1 to change NMDA versus AMPA receptor levels, and the effect is carried by short cytoplasmic motifs rather than by the channel. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors |
| GO:0099175 regulation of postsynapse organization | IEA GO_REF:0000107 | ACCEPT | Summary: GluD1 organises the postsynaptic side of the synapses it occupies. Reason: Supported by the receptor-content changes downstream of trans-synaptic signalling and by the loss of specific presynaptic inputs when GluD1 is deleted from the striatum. Note this occurs without changing synapse numbers in hippocampus, so it is organisation rather than synaptogenesis. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:31945419 Conditional deletion of GluD1 from the striatum led to a selective loss of thalamic, but not cortical, terminals, and reduced glutamatergic neurotransmission. |
| GO:0099538 synaptic signaling via neuropeptide | IEA GO_REF:0000120 | MODIFY | Summary: Almost certainly intended to record cerebellin-mediated trans-synaptic signalling; GO:0099557 states that without implying a neuropeptide. Reason: No neuropeptide is involved anywhere in the GluD1 literature. The GO definition is looser than the label ("Cell-cell signaling to or from a synapse, mediated by a peptide"), which is presumably how a curator reached it for cerebellin-mediated trans-synaptic signalling - cerebellin-1 is a small secreted protein. But GO:0099557 says exactly that, is already annotated on this gene from the same body of work, and does not carry the misleading "neuropeptide" label. Re-pointed rather than removed, because the underlying biology being recorded is real. Applied uniformly to the IEA, ISS and IDA rows for this term. The IDA row is additionally problematic because its reference (PMID:27276689) concerns mGlu1-triggered opening of GluD2 and involves no peptide at all. Proposed replacements: trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins PMID:39052831 The transsynaptic triad of Nrxn-Cbln-GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. |
| GO:0099557 trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission | IEA GO_REF:0000120 | ACCEPT | Summary: Trans-synaptic signalling through the neurexin-cerebellin-GluD1 complex is the core process GluD1 participates in. Reason: This is the core biological process for GluD1 and it is recorded at exactly the right grain. Presynaptic neurexin-cerebellin complexes bind the GluD1 amino-terminal domain and the signal is relayed across the membrane to change postsynaptic receptor content; the transduction demonstrably bypasses the channel, since constructs in which the whole transmembrane region is swapped for an unrelated segment remain fully functional. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors PMID:34135511 Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture |
| GO:1904315 transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential | IEA GO_REF:0000107 | UNDECIDED | Summary: Same unresolved claim as the IBA row: direct transmitter gating of GluD1 is asserted but not established. Reason: This is the central contested claim about GluD1 and the evidence is genuinely split, so neither ACCEPT nor REMOVE is honest. AGAINST: a dedicated study with the controls the original glycine/D-serine gating reports lacked found identical currents in naive HEK293 cells and in GluD2-null Purkinje neurons, and concluded that extracellular ligands do not directly gate wild-type GluD; UniProt carries this as an explicit CAUTION on Q9ULK0. The GABA effect that GluD1 does mediate is stated by its discoverers to be non-ionotropic. A 2026 review from the field says GluD1 lacks classical ion channel activity. FOR: a 2026 report describes ACh-evoked, NASPM-sensitive currents in medium spiny neurons that are absent in GluD1 knockouts and rescued by GluD1 re-expression - although those authors themselves hedge ("suggesting potential conductance"), and their ligand-binding evidence is an indirect conformational assay. Separately, GluD1 unquestionably carries current in native neurons, but tonically and/or downstream of Gq-coupled receptors, which is not what "transmitter-gated" means. A further proposal is that the channel is simply silent at room temperature because of a high energetic activation barrier. The phylogenetic node behind this IBA (PANTHER:PTN001826301) spans the whole iGluR family including GRID2, so the node placement is not the problem; whether the delta branch retained direct transmitter gating is the problem. This row is an Ensembl-Compara transfer from mouse Grid1 (UniProtKB:Q61627), which inherits the same open question rather than settling it. Supporting Evidence: PMID:39052831 these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels PMID:41345253 primarily due to its lack of classical ion channel activity PMID:42270762 produced current responses in medium spiny neurons (MSNs) that were sensitive to the GluD1-channel blocker NASPM PMID:32234214 GluD1R-channels are constitutively active under basal conditions carrying tonic inward current |
| GO:0016917 GABA receptor activity | IDA PMID:38060673 GluD1 binds GABA and controls inhibitory plasticity. | ACCEPT | Summary: GluD1 binds GABA and transduces it non-ionotropically into lasting potentiation of inhibitory transmission; the general GABA receptor activity term fits, the GABA-A child would not. Reason: This looks like the most surprising annotation on the gene and is in fact one of the best supported. Structural and functional work shows GluD1 binds GABA in its ligand-binding domain and that GABA binding produces a lasting change in synaptic strength. Crucially, the GO definition of GO:0016917 - combining with GABA and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity - does not require an ion current, so it fits even though the authors are explicit that the mechanism is non-ionotropic and requires trans-synaptic anchoring. The ionotropic child term GO:0004890 GABA-A receptor activity would NOT be appropriate. Retained as a core molecular function. Supporting Evidence: PMID:38060673 we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs PMID:38060673 GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring PMID:38060673 The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors. PMID:41345253 This binding does not trigger ion flux through the receptor but initiates a non-ionotropic signaling cascade that enhances inhibitory synaptic transmission. |
| GO:0031914 negative regulation of synaptic plasticity | IDA PMID:38060673 GluD1 binds GABA and controls inhibitory plasticity. | MODIFY | Summary: The cited experiment shows long-lasting ENHANCEMENT of GABAergic transmission; the sign of the chosen term does not match the direction of the measured effect. Reason: PMID:38060673 reports that GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in adult mouse hippocampus - a potentiation of inhibitory synapses. The curator may have reasoned that stronger inhibition dampens plasticity at excitatory synapses, but that is an inference about a downstream consequence rather than the assayed result, and it inverts the sign of what was measured. GO:0032230 records the observed effect directly. The gene separately carries GO:0048167 regulation of synaptic plasticity, which remains appropriate and unsigned. Not removed: the underlying experimental observation is sound and was made on this gene. Proposed replacements: positive regulation of synaptic transmission, GABAergic Supporting Evidence: PMID:38060673 GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring PMID:41345253 This binding does not trigger ion flux through the receptor but initiates a non-ionotropic signaling cascade that enhances inhibitory synaptic transmission. |
| GO:0045211 postsynaptic membrane | IDA PMID:38060673 GluD1 binds GABA and controls inhibitory plasticity. | ACCEPT | Summary: Direct localisation of GluD1 to the postsynaptic membrane. Reason: Consistent with the IEA row for the same term and with UniProt subcellular location. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway | IDA PMID:27276689 mGlu1 receptor canonical signaling pathway contributes to th... | KEEP AS NON CORE | Summary: GluD current is opened downstream of the Gq-PLC-PKC cascade, so GluD is an effector within this pathway rather than a receptor that initiates it. Reason: The cited work shows that stimulating mGlu1 opens the GluD channel through Gaq, PLC and PKC. involved_in is defensible for a terminal effector of the pathway, but the annotation should not be read as GluD1 activating phospholipase C - it does not. Two further caveats are recorded honestly rather than used to overturn the annotation: the direct recordings in that paper are of GluD2 in HEK293 cells and cerebellar Purkinje cells, and the analogous GluD1 currents in dorsal raphe neurons turn out to have a large G-protein-independent tonic component. Kept as contextual, not core. Supporting Evidence: PMID:27276689 inhibition of the downstream components of the mGlu1 canonical signaling pathway PLC and PKC with U73122 and GF109203X, respectively, strongly reduced the DHPG-induced GluD2 current PMID:27276689 the opening of the GluD2 channel by mGlu1 receptor mobilizes the canonical Gq-PLC-PKC pathway PMID:37154294 GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus. |
| GO:0030545 signaling receptor regulator activity | IDA PMID:34135511 GluD1 is a signal transduction device disguised as an ionotr... | ACCEPT | Summary: GluD1 regulates the levels and activity of other postsynaptic receptors as part of the trans-synaptic complex; this is its best-supported molecular role. Reason: Of everything GOA asserts about the molecular function of GluD1, this is the one that best matches the experimental picture. Within the neurexin-cerebellin-GluD1 trans-synaptic complex, GluD1 regulates the abundance and activity of other postsynaptic receptors (NMDA and AMPA receptors), and it does so through its cytoplasmic tail rather than through its pore - chimeras in which the entire transmembrane/channel region is replaced by an unrelated transmembrane segment retain full activity. The contributes_to qualifier is appropriate, since the regulation requires the assembled trans-synaptic complex. This IDA row is the primary evidence; the Ensembl IEA row for the same term is a transfer of the mouse equivalent. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors PMID:34135511 Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture |
| GO:0045202 synapse | IDA PMID:34135511 GluD1 is a signal transduction device disguised as an ionotr... | ACCEPT | Summary: GluD1 acts at synapses. Reason: Concordant with the IEA row for the same term; the specific synapse-type annotations are more informative. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers |
| GO:0098820 trans-synaptic protein complex | ISS GO_REF:0000024 | ACCEPT | Summary: GluD1 is the postsynaptic component of the neurexin-cerebellin-GluD trans-synaptic complex. Reason: This is the defining assembly for GluD1: the amino-terminal domain binds secreted cerebellin-1/2, which in turn bind presynaptic neurexins bearing the splice-site-4 insert, bridging the cleft. Recorded with part_of, which is correct. This complex, not the AMPA receptor complex, is the complex GluD1 belongs to. Transferred from mouse Grid1 (MGI:MGI:95812), where the complex was characterised; the human orthologue is fully conserved in the relevant amino-terminal domain. Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins PMID:39052831 The transsynaptic triad of Nrxn-Cbln-GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. |
| GO:0098839 postsynaptic density membrane | ISS GO_REF:0000024 | ACCEPT | Summary: GluD1 is a postsynaptic density protein. Reason: Concordant with the IBA and IEA rows for the same term. Supporting Evidence: PMID:42270762 GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum |
| GO:0099530 G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential | IDA PMID:27276689 mGlu1 receptor canonical signaling pathway contributes to th... | MODIFY | Summary: GluD1 has the ionotropic glutamate receptor fold, not a seven-transmembrane GPCR fold; the GPCR in the cited experiment is mGlu1, and GluD is the channel it opens. Reason: GluD1 is not a G-protein-coupled receptor. It is a tetrameric assembly of subunits with three transmembrane segments and a re-entrant pore loop, the canonical ionotropic glutamate receptor fold - not a seven-transmembrane GPCR - and no G-protein coupling by GluD1 itself has ever been reported. What the cited paper actually shows is the opposite arrangement: a genuine GPCR (mGlu1) signals through Gaq, PLC and PKC to open the GluD channel. The GPCR activity belongs to mGlu1; GluD is the downstream effector. This is a role conflation in which the effector has been annotated as the agent. A second caveat, recorded but not used as the basis for the action: the direct electrophysiology in that paper is on GluD2 in HEK293 cells and Purkinje cells. Following project policy this experimental annotation is re-pointed rather than removed - the underlying observation, that a GluD cation current is opened downstream of Gq signalling, is sound and is what GO:0005261 records. Proposed replacements: monoatomic cation channel activity Supporting Evidence: PMID:27276689 inhibition of the downstream components of the mGlu1 canonical signaling pathway PLC and PKC with U73122 and GF109203X, respectively, strongly reduced the DHPG-induced GluD2 current PMID:27276689 the opening of the GluD2 channel by mGlu1 receptor mobilizes the canonical Gq-PLC-PKC pathway PMID:32234214 GluD1R-channels are constitutively active under basal conditions carrying tonic inward current |
| GO:0099538 synaptic signaling via neuropeptide | ISS GO_REF:0000024 | MODIFY | Summary: Almost certainly intended to record cerebellin-mediated trans-synaptic signalling; GO:0099557 states that without implying a neuropeptide. Reason: No neuropeptide is involved anywhere in the GluD1 literature. The GO definition is looser than the label ("Cell-cell signaling to or from a synapse, mediated by a peptide"), which is presumably how a curator reached it for cerebellin-mediated trans-synaptic signalling - cerebellin-1 is a small secreted protein. But GO:0099557 says exactly that, is already annotated on this gene from the same body of work, and does not carry the misleading "neuropeptide" label. Re-pointed rather than removed, because the underlying biology being recorded is real. Applied uniformly to the IEA, ISS and IDA rows for this term. The IDA row is additionally problematic because its reference (PMID:27276689) concerns mGlu1-triggered opening of GluD2 and involves no peptide at all. Proposed replacements: trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission Supporting Evidence: PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins PMID:39052831 The transsynaptic triad of Nrxn-Cbln-GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. |
| GO:0099538 synaptic signaling via neuropeptide | IDA PMID:27276689 mGlu1 receptor canonical signaling pathway contributes to th... | MODIFY | Summary: Almost certainly intended to record cerebellin-mediated trans-synaptic signalling; GO:0099557 states that without implying a neuropeptide. Reason: No neuropeptide is involved anywhere in the GluD1 literature. The GO definition is looser than the label ("Cell-cell signaling to or from a synapse, mediated by a peptide"), which is presumably how a curator reached it for cerebellin-mediated trans-synaptic signalling - cerebellin-1 is a small secreted protein. But GO:0099557 says exactly that, is already annotated on this gene from the same body of work, and does not carry the misleading "neuropeptide" label. Re-pointed rather than removed, because the underlying biology being recorded is real. Applied uniformly to the IEA, ISS and IDA rows for this term. The IDA row is additionally problematic because its reference (PMID:27276689) concerns mGlu1-triggered opening of GluD2 and involves no peptide at all. Proposed replacements: trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission Supporting Evidence: PMID:27276689 the opening of the GluD2 channel by mGlu1 receptor mobilizes the canonical Gq-PLC-PKC pathway PMID:34135511 assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins |
| GO:0099557 trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission | IDA PMID:34135511 GluD1 is a signal transduction device disguised as an ionotr... | ACCEPT | Summary: Trans-synaptic signalling through the neurexin-cerebellin-GluD1 complex is the core process GluD1 participates in. Reason: This is the core biological process for GluD1 and it is recorded at exactly the right grain. Presynaptic neurexin-cerebellin complexes bind the GluD1 amino-terminal domain and the signal is relayed across the membrane to change postsynaptic receptor content; the transduction demonstrably bypasses the channel, since constructs in which the whole transmembrane region is swapped for an unrelated segment remain fully functional. Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:34135511 minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors PMID:34135511 Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture |
| GO:1904315 transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential | ISS GO_REF:0000024 | UNDECIDED | Summary: Same unresolved claim as the IBA and IEA rows: direct transmitter gating of GluD1 is asserted but not established. Reason: This is the central contested claim about GluD1 and the evidence is genuinely split, so neither ACCEPT nor REMOVE is honest. AGAINST: a dedicated study with the controls the original glycine/D-serine gating reports lacked found identical currents in naive HEK293 cells and in GluD2-null Purkinje neurons, and concluded that extracellular ligands do not directly gate wild-type GluD; UniProt carries this as an explicit CAUTION on Q9ULK0. The GABA effect that GluD1 does mediate is stated by its discoverers to be non-ionotropic. A 2026 review from the field says GluD1 lacks classical ion channel activity. FOR: a 2026 report describes ACh-evoked, NASPM-sensitive currents in medium spiny neurons that are absent in GluD1 knockouts and rescued by GluD1 re-expression - although those authors themselves hedge ("suggesting potential conductance"), and their ligand-binding evidence is an indirect conformational assay. Separately, GluD1 unquestionably carries current in native neurons, but tonically and/or downstream of Gq-coupled receptors, which is not what "transmitter-gated" means. A further proposal is that the channel is simply silent at room temperature because of a high energetic activation barrier. The phylogenetic node behind this IBA (PANTHER:PTN001826301) spans the whole iGluR family including GRID2, so the node placement is not the problem; whether the delta branch retained direct transmitter gating is the problem. This row is a curator-judged transfer from mouse Grid1 (MGI:MGI:95812); the mouse orthologue carries the same unresolved question, so the transfer propagates the uncertainty rather than resolving it. Supporting Evidence: PMID:39052831 these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels PMID:41345253 primarily due to its lack of classical ion channel activity PMID:42270762 produced current responses in medium spiny neurons (MSNs) that were sensitive to the GluD1-channel blocker NASPM PMID:37154294 GluD1R carries a G-protein-independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus. |
| GO:0035176 social behavior | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Behavioural consequence of GluD1 loss in rodents; real but distal to the molecular function. Reason: Supported by knockout phenotypes in the mouse orthologue and consistent with the human genetics of the locus, but this is an organism-level consequence several steps removed from the molecular activity, and it is not specific: GluD1 loss affects behavioural flexibility, anxiety-like behaviour and compulsive behaviours as well. Kept as contextual, not core. Transferred from mouse Grid1 (UniProtKB:Q61627). Supporting Evidence: PMID:31945419 selective ablation of GluD1 from the dorsal striatum impairs behavioral flexibility in a water T-maze task PMID:32234214 loss of dorsal raphe GluD1R-channels produces an anxiogenic phenotype |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: A hit in a urinary exosome proteome; not a meaningful location for a brain postsynaptic receptor. Reason: High-throughput mass-spectrometry detection in exosomes purified from urine (PMID:19056867). GluD1 expression is essentially restricted to the central nervous system and its established location is the postsynaptic membrane; a single proteome-scale detection in urinary vesicles is far more likely to reflect identification noise than a real localisation, and it has no functional interpretation. Typical of the non-specific exosome annotations generated by this class of dataset. |
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Download this section (compressed HTML)Q: Is the acetylcholine-evoked, NASPM-sensitive current reported at striatal cholinergic synapses a current through the GluD1 pore, or a GluD1-dependent current carried by something else? The knockout and rescue controls establish GluD1 dependence but not that GluD1 is the conducting species, and the authors themselves write only of "potential conductance".
Q: How can the same group report, in the same year, that GluD1 is an acetylcholine receptor with measurable currents and that GluD1 has a "lack of classical ion channel activity"? Is the intended reconciliation that GluD1 conducts only when trans-synaptically anchored, or only at physiological temperature, or only in specific circuits?
Q: Does the delta-receptor pore require physiological temperature to open, as proposed for GluD2 on thermodynamic grounds? If so, how much of the twenty-year "orphan receptor" literature is an artefact of recording at room temperature?
Q: Should GO create a molecular-function term for a receptor that binds a neurotransmitter and transduces the signal without conducting ions? GO:0016917 GABA receptor activity happens to accommodate this because its definition does not mention a channel, but that is fortuitous rather than deliberate, and there is no general term for non-ionotropic neurotransmitter reception.
Q: What couples Gq-PLC-PKC signalling to opening of the GluD channel - is there a phosphorylation site on the GluD cytoplasmic tail, or does an intermediary protein act on the pore?
Q: Given that GluD1 sits at glutamatergic, GABAergic and cholinergic synapses and binds GABA, D-serine, glycine and possibly acetylcholine, is the correct framing that GluD1 is a promiscuous sensor whose output is set by its trans-synaptic partners rather than by its ligand?
Experiment: Record acetylcholine-evoked currents in medium spiny neurons from mice in which GluD1 has been replaced by a pore-dead knock-in (a selectivity-filter or Q/R-site mutant that traffics and binds cerebellin normally) rather than deleted. If the current survives loss of the pore while trans-synaptic function is intact, GluD1 is required but is not the conducting species; if it is abolished while cerebellin binding is unaffected, GluD1 conducts.
Hypothesis: GluD1 itself is the conducting species in acetylcholine-evoked currents at striatal cholinergic synapses.
Experiment: Repeat the glycine/D-serine/GABA/acetylcholine application experiments on wild-type GluD1 in parallel at 22 and 37 degrees C, always with untransfected cells and GluD1-null neurons recorded in the same sessions as required by PMID:39052831. Fit the temperature dependence to extract an activation energy and test whether it matches the barrier proposed for GluD2.
Hypothesis: Direct ligand gating of wild-type GluD1 is masked at room temperature by a high activation energy barrier.
Experiment: Use the reported differences in binding orientation to design binding-site mutants that abolish GABA binding while preserving acetylcholine binding and vice versa (starting from R526K and D742A, which abolish the GABA effect), then test each mutant for inhibitory potentiation in hippocampus and for acetylcholine-evoked current in striatum. This separates the non-ionotropic GABA signal from the putative cholinergic conductance in one background.
Hypothesis: The GABA, D-serine and acetylcholine effects on GluD1 are separable at the level of the binding site.
Experiment: Map PKC phosphosites on the GluD1 cytoplasmic tail by mass spectrometry after mGlu1 or alpha-1 adrenergic stimulation, then test phospho-null and phospho-mimetic tails for their effect on the tonic and Gq-augmented currents in dorsal raphe neurons, and separately for their effect on NMDA and AMPA receptor levels - determining whether the channel and organiser outputs share a regulatory node.
Hypothesis: The Gq-PLC-PKC cascade opens the GluD channel through phosphorylation of the GluD cytoplasmic tail.
Experiment: Native-source co-immunoprecipitation and blue-native PAGE from mouse forebrain using GluD1 and GRIA1-4 antibodies, with GluD1-null tissue as the specificity control, to test directly whether GluD1 is ever found in a complex with AMPA receptor subunits or only in cerebellin/neurexin assemblies.
Hypothesis: GluD1 does not occupy AMPA receptor complexes, contrary to the propagated annotation.
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