grlE

UniProt ID: Q54ET0
Organism: Dictyostelium discoideum
Review Status: COMPLETE
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Gene Description

GrlE (also called DdmGluPR or GluPR) is a class C (family 3) seven-transmembrane G-protein-coupled receptor of the GABA-B/metabotropic glutamate receptor family in the social amoeba Dictyostelium discoideum. It has a large extracellular Venus-flytrap ligand-binding domain followed by seven transmembrane helices and a cytoplasmic tail, and it localizes to the plasma membrane. GrlE serves as the receptor for GABA during multicellular development, when prespore cells approach the top of the fruiting body and GABA released from prespore cells acts through GrlE to trigger release of the SDF-2 precursor AcbA, which together with exposure of the TagC protease on prestalk cells drives terminal differentiation and encapsulation of spore cells, with signaling relayed through PI3-kinase and the PKB-related kinase PkbR1. Glutamate, whose alpha-carboxyl and alpha-amino binding residues are conserved in the receptor, acts as a competitive antagonist of GABA at GrlE. GrlE is also implicated in early development, where loss of the gene causes faster growth to higher cell densities, delayed aggregation upon starvation, and impaired chemotaxis toward cAMP.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004965 G protein-coupled GABA receptor activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference that GrlE is a G-protein-coupled GABA receptor is strongly corroborated by direct experimental evidence in Dictyostelium, where GrlE was identified as the receptor for GABA. This is the core molecular function of the protein.
Reason: GrlE is the GABA(B)-like GPCR that mediates the GABA response in Dictyostelium; the IBA inference agrees with the experimental IMP annotation from the same gene.
Supporting Evidence:
PMID:16672332
The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
GO:0007214 gamma-aminobutyric acid signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: GrlE transduces a GABA signal that induces terminal spore differentiation, so involvement in a GABA signaling pathway is well supported and represents a core biological role.
Reason: Consistent with the experimental demonstration that GABA acts through GrlE to induce release of the SDF-2 precursor AcbA and drive encapsulation.
Supporting Evidence:
PMID:16672332
GABA induces the release of the precursor of SDF-2, AcbA, from prespore cells
GO:0038039 G protein-coupled receptor heterodimeric complex
IBA
GO_REF:0000033 		REMOVE
Summary: This term is transferred by phylogeny from mammalian GABA(B) receptors, which are obligate GABABR1/GABABR2 heterodimers. There is no evidence that GrlE forms an analogous heterodimeric receptor complex in Dictyostelium, which lacks the mammalian two-subunit GABA(B) architecture.
Reason: The obligate heterodimer is a specific feature of the mammalian GABA(B) receptor pair and does not transfer to this divergent single-gene Dictyostelium receptor; there is no experimental support for a heterodimeric complex here. This is an IBA over-propagation.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: COMPARTMENT OR COMPLEX MISMATCH
Sources checked:
PANTHER:PTN000828857 · PANTHER node for class-C / GABA(B) G-protein-coupled receptors SUPPORTS SOURCE BUT NOT TARGET
Obligate heterodimeric-complex membership is a specific feature of the mammalian GABABR1/GABABR2 pair and does not transfer to the single-gene Dictyostelium receptor
UniProtKB:Q9UBS5 · human GABA(B) receptor subunit 1 (GABBR1) SUPPORTS SOURCE BUT NOT TARGET
Forms an obligate heterodimer with GABBR2 in mammals; Dictyostelium lacks this two-subunit architecture
Supporting Evidence:
PMID:16672332
The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
GO:0004930 G protein-coupled receptor activity
IEA
GO_REF:0000002 		MODIFY
Summary: Correct but general InterPro2GO annotation. The specific child term G protein-coupled GABA receptor activity (GO:0004965) is available and better captures the demonstrated function.
Reason: GrlE is a GPCR, so the general term is not wrong, but the more specific GABA receptor activity term is supported by experimental evidence and should be used instead.
Supporting Evidence:
PMID:16672332
The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
GO:0004965 G protein-coupled GABA receptor activity
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro2GO annotation from the GPCR family 3 GABA-B signature (IPR002455), redundant with the experimentally supported IMP/IBA annotations to the same term. Correct and represents the core function.
Reason: The domain-based inference agrees with the experimental evidence that GrlE is the Dictyostelium GABA receptor.
Supporting Evidence:
PMID:16672332
The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
GO:0007186 G protein-coupled receptor signaling pathway
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Correct but general InterPro2GO annotation describing the mechanistic pathway class. The more specific GABA signaling pathway (GO:0007214) is experimentally supported for this gene.
Reason: GrlE signals as a GPCR, so this parent term is accurate, but it is subsumed by the more informative GABA signaling pathway annotation and is not the most specific description of the function.
Supporting Evidence:
PMID:16672332
The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
GO:0016020 membrane
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Correct but general localization. GrlE is a multi-pass membrane protein; direct evidence localizes it specifically to the plasma membrane (GO:0005886), which is the more informative term.
Reason: True as far as it goes, but the plasma membrane annotation from direct evidence is more specific and preferable.
Supporting Evidence:
PMID:16527814
DdmGluPR was localized to the plasma membrane of axenically grown Ax-2 cells expressed as a green fluorescent protein fusion protein
GO:0016595 glutamate binding
IDA
PMID:16672332
GABA induces terminal differentiation of Dictyostelium throu... 		KEEP AS NON CORE
Summary: Glutamate acts at GrlE as a competitive inhibitor of GABA, and the residues that bind the alpha-carboxyl and alpha-amino groups of glutamate are conserved in the receptor, consistent with glutamate binding to the ligand-binding domain. Binding is retained but is antagonistic rather than the core activating function.
Reason: Glutamate binding is experimentally supported (glutamate competes with GABA), but at GrlE glutamate is an antagonist that inhibits the GABA response, so this is a secondary/modulatory feature rather than the core function.
Supporting Evidence:
PMID:16672332
Glutamate acts as a competitive inhibitor of GABA functions in Dictyostelium
GO:1901261 regulation of sorocarp spore cell differentiation
IMP
PMID:16672332
GABA induces terminal differentiation of Dictyostelium throu... 		ACCEPT
Summary: GABA acting through GrlE induces terminal differentiation and encapsulation of spore cells by triggering AcbA/SDF-2 release. This is a core developmental role of the receptor.
Reason: Directly supported by the disruption and induction phenotypes showing GrlE-dependent GABA control of prespore encapsulation.
Supporting Evidence:
PMID:16672332
they rapidly encapsulate in response to the signalling peptide SDF-2
PMID:16672332
GABA induces the release of the precursor of SDF-2, AcbA, from prespore cells
GO:0005886 plasma membrane
IDA
PMID:16527814
A metabotropic glutamate receptor family gene in Dictyosteli... 		ACCEPT
Summary: GFP-tagged GrlE localizes to the plasma membrane, the expected location for a signal-transducing GPCR. Well supported by direct evidence.
Reason: Direct localization evidence places the receptor at the plasma membrane, where it is active in ligand sensing.
Supporting Evidence:
PMID:16527814
DdmGluPR was localized to the plasma membrane of axenically grown Ax-2 cells expressed as a green fluorescent protein fusion protein
GO:0004965 G protein-coupled GABA receptor activity
IMP
PMID:16672332
GABA induces terminal differentiation of Dictyostelium throu... 		ACCEPT
Summary: Direct genetic evidence identifies GrlE as the GABA receptor in Dictyostelium (null cells fail to respond to GABA). This is the core molecular function.
Reason: Experimental (IMP) demonstration that GrlE mediates the cellular response to GABA supports this as the primary molecular function.
Supporting Evidence:
PMID:16672332
The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
GO:0007214 gamma-aminobutyric acid signaling pathway
IMP
PMID:16672332
GABA induces terminal differentiation of Dictyostelium throu... 		ACCEPT
Summary: GrlE initiates a GABA signal transduction pathway (relayed via PI3 kinase and PkbR1) that controls SDF-2 production and terminal differentiation. Core biological process for this gene.
Reason: Experimentally supported; GABA signaling through GrlE is the defining pathway in which the gene acts.
Supporting Evidence:
PMID:16672332
The signal transduction pathway from GABA/GrlE appears to be mediated by PI3 kinase and the PKB-related protein kinase PkbR1
GO:0008066 glutamate receptor activity
IMP
PMID:16672332
GABA induces terminal differentiation of Dictyostelium throu... 		KEEP AS NON CORE
Summary: GrlE was originally identified as a metabotropic glutamate receptor-like protein and binds glutamate, but functionally glutamate acts as a competitive inhibitor of the GABA response rather than as an activating agonist. The glutamate-responsive role is secondary to the core GABA receptor function.
Reason: Glutamate is a genuine ligand of GrlE but acts antagonistically to GABA; classifying GrlE primarily as a glutamate receptor overstates this modulatory role, so it is retained as non-core rather than as the core molecular function.
Supporting Evidence:
PMID:16672332
Glutamate acts as a competitive inhibitor of GABA functions in Dictyostelium
GO:0031152 aggregation involved in sorocarp development
IMP
PMID:16527814
A metabotropic glutamate receptor family gene in Dictyosteli... 		KEEP AS NON CORE
Summary: GrlE-null cells show delayed aggregate formation upon starvation, implicating the receptor in early developmental aggregation. This is a distinct early-development role from its late GABA/spore function.
Reason: Supported by the disruption phenotype, but this early aggregation role is a pleiotropic early-development function upstream of the receptor's core late GABA-mediated activity.
Supporting Evidence:
PMID:16527814
DdmGluPR-null cells exhibited delayed aggregates formation upon starvation and impaired chemotaxis toward cAMP
GO:0043327 chemotaxis to cAMP
IMP
PMID:16527814
A metabotropic glutamate receptor family gene in Dictyosteli... 		KEEP AS NON CORE
Summary: GrlE-null cells display impaired chemotaxis toward cAMP and altered induction of cAMP-signaling components (cAR1, aca), implicating the receptor in early cAMP-driven aggregation. A pleiotropic early-development role rather than the core function.
Reason: The chemotaxis phenotype is experimentally supported but reflects an indirect, early-development role of GrlE upstream of cAMP signaling, not its core GABA receptor activity.
Supporting Evidence:
PMID:16527814
DdmGluPR-null cells exhibited delayed aggregates formation upon starvation and impaired chemotaxis toward cAMP

Core Functions

GrlE is a plasma-membrane class C G-protein-coupled receptor that functions as the receptor for GABA in Dictyostelium, initiating a GABA signaling pathway that triggers AcbA/SDF-2 release and drives terminal differentiation and encapsulation of spore cells during culmination.

Molecular Function:
G protein-coupled GABA receptor activity
Directly Involved In:
gamma-aminobutyric acid signaling pathway
Cellular Locations:
plasma membrane
Supporting Evidence:
  • PMID:16672332
    The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors
  • PMID:16672332
    GABA induces the release of the precursor of SDF-2, AcbA, from prespore cells
  • PMID:16527814
    DdmGluPR was localized to the plasma membrane of axenically grown Ax-2 cells expressed as a green fluorescent protein fusion protein

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:16527814
A metabotropic glutamate receptor family gene in Dictyostelium discoideum.
  • GrlE/DdmGluPR is a metabotropic glutamate receptor family GPCR that localizes to the plasma membrane.
    "DdmGluPR was localized to the plasma membrane of axenically grown Ax-2 cells expressed as a green fluorescent protein fusion protein"
  • The alpha-carboxyl and alpha-amino glutamate-binding residues are conserved in GrlE, but the gamma-carboxyl-interacting residues are not.
    "the residues of mGluRs involved in the binding of the alpha-carboxylic and alpha-amino groups of glutamate were well conserved in DdmGluPR"
  • GrlE-null cells grow faster to higher densities, aggregate late, and show impaired chemotaxis toward cAMP, implicating GrlE in early development.
    "DdmGluPR-null cells exhibited delayed aggregates formation upon starvation and impaired chemotaxis toward cAMP"
PMID:16672332
GABA induces terminal differentiation of Dictyostelium through a GABAB receptor.
  • GrlE is the seven-transmembrane GABA(B)-like receptor for GABA in Dictyostelium.
    "The receptor for GABA in Dictyostelium, GrlE, is a seven-transmembrane G-protein-coupled receptor that is most similar to GABA(B) receptors"
  • GABA acting through GrlE induces release of the SDF-2 precursor AcbA from prespore cells to drive terminal spore differentiation.
    "GABA induces the release of the precursor of SDF-2, AcbA, from prespore cells"
  • GABA/GrlE signaling is relayed through PI3 kinase and the PKB-related kinase PkbR1, and glutamate competitively inhibits it.
    "The signal transduction pathway from GABA/GrlE appears to be mediated by PI3 kinase and the PKB-related protein kinase PkbR1"

Suggested Questions for Experts

Q: Which heterotrimeric G-protein alpha subunit does GrlE couple to when GABA triggers the PI3-kinase / PkbR1 relay that drives AcbA/SDF-2 release during culmination?

📄 View Raw YAML

 
id: Q54ET0
gene_symbol: grlE
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: GrlE (also called DdmGluPR or GluPR) is a class C (family 3)
  seven-transmembrane G-protein-coupled receptor of the GABA-B/metabotropic
  glutamate receptor family in the social amoeba Dictyostelium discoideum. It
  has a large extracellular Venus-flytrap ligand-binding domain followed by
  seven transmembrane helices and a cytoplasmic tail, and it localizes to the
  plasma membrane. GrlE serves as the receptor for GABA during multicellular
  development, when prespore cells approach the top of the fruiting body and
  GABA released from prespore cells acts through GrlE to trigger release of the
  SDF-2 precursor AcbA, which together with exposure of the TagC protease on
  prestalk cells drives terminal differentiation and encapsulation of spore
  cells, with signaling relayed through PI3-kinase and the PKB-related kinase
  PkbR1. Glutamate, whose alpha-carboxyl and alpha-amino binding residues are
  conserved in the receptor, acts as a competitive antagonist of GABA at GrlE.
  GrlE is also implicated in early development, where loss of the gene causes
  faster growth to higher cell densities, delayed aggregation upon starvation,
  and impaired chemotaxis toward cAMP.
existing_annotations:
- term:
    id: GO:0004965
    label: G protein-coupled GABA receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference that GrlE is a G-protein-coupled GABA
      receptor is strongly corroborated by direct experimental evidence in
      Dictyostelium, where GrlE was identified as the receptor for GABA. This is
      the core molecular function of the protein.
    action: ACCEPT
    reason: GrlE is the GABA(B)-like GPCR that mediates the GABA response in
      Dictyostelium; the IBA inference agrees with the experimental IMP
      annotation from the same gene.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
        seven-transmembrane G-protein-coupled receptor that is most similar to
        GABA(B) receptors
- term:
    id: GO:0007214
    label: gamma-aminobutyric acid signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: GrlE transduces a GABA signal that induces terminal spore
      differentiation, so involvement in a GABA signaling pathway is well
      supported and represents a core biological role.
    action: ACCEPT
    reason: Consistent with the experimental demonstration that GABA acts
      through GrlE to induce release of the SDF-2 precursor AcbA and drive
      encapsulation.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: GABA induces the release of the precursor of SDF-2, AcbA,
        from prespore cells
- term:
    id: GO:0038039
    label: G protein-coupled receptor heterodimeric complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: This term is transferred by phylogeny from mammalian GABA(B)
      receptors, which are obligate GABABR1/GABABR2 heterodimers. There is no
      evidence that GrlE forms an analogous heterodimeric receptor complex in
      Dictyostelium, which lacks the mammalian two-subunit GABA(B) architecture.
    action: REMOVE
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000828857
        source_label: "PANTHER node for class-C / GABA(B) G-protein-coupled receptors"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "Obligate heterodimeric-complex membership is a specific feature of the mammalian GABABR1/GABABR2 pair and does not transfer to the single-gene Dictyostelium receptor"
      - source_id: UniProtKB:Q9UBS5
        source_label: "human GABA(B) receptor subunit 1 (GABBR1)"
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: "Forms an obligate heterodimer with GABBR2 in mammals; Dictyostelium lacks this two-subunit architecture"
    reason: The obligate heterodimer is a specific feature of the mammalian
      GABA(B) receptor pair and does not transfer to this divergent single-gene
      Dictyostelium receptor; there is no experimental support for a
      heterodimeric complex here. This is an IBA over-propagation.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
        seven-transmembrane G-protein-coupled receptor that is most similar to
        GABA(B) receptors
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Correct but general InterPro2GO annotation. The specific child term
      G protein-coupled GABA receptor activity (GO:0004965) is available and
      better captures the demonstrated function.
    action: MODIFY
    reason: GrlE is a GPCR, so the general term is not wrong, but the more
      specific GABA receptor activity term is supported by experimental evidence
      and should be used instead.
    proposed_replacement_terms:
    - id: GO:0004965
      label: G protein-coupled GABA receptor activity
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
        seven-transmembrane G-protein-coupled receptor that is most similar to
        GABA(B) receptors
- term:
    id: GO:0004965
    label: G protein-coupled GABA receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO annotation from the GPCR family 3 GABA-B signature
      (IPR002455), redundant with the experimentally supported IMP/IBA
      annotations to the same term. Correct and represents the core function.
    action: ACCEPT
    reason: The domain-based inference agrees with the experimental evidence that
      GrlE is the Dictyostelium GABA receptor.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
        seven-transmembrane G-protein-coupled receptor that is most similar to
        GABA(B) receptors
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Correct but general InterPro2GO annotation describing the
      mechanistic pathway class. The more specific GABA signaling pathway
      (GO:0007214) is experimentally supported for this gene.
    action: KEEP_AS_NON_CORE
    reason: GrlE signals as a GPCR, so this parent term is accurate, but it is
      subsumed by the more informative GABA signaling pathway annotation and is
      not the most specific description of the function.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
        seven-transmembrane G-protein-coupled receptor that is most similar to
        GABA(B) receptors
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Correct but general localization. GrlE is a multi-pass membrane
      protein; direct evidence localizes it specifically to the plasma membrane
      (GO:0005886), which is the more informative term.
    action: KEEP_AS_NON_CORE
    reason: True as far as it goes, but the plasma membrane annotation from
      direct evidence is more specific and preferable.
    supported_by:
    - reference_id: PMID:16527814
      supporting_text: DdmGluPR was localized to the plasma membrane of axenically
        grown Ax-2 cells expressed as a green fluorescent protein fusion protein
- term:
    id: GO:0016595
    label: glutamate binding
  evidence_type: IDA
  original_reference_id: PMID:16672332
  qualifier: enables
  review:
    summary: Glutamate acts at GrlE as a competitive inhibitor of GABA, and the
      residues that bind the alpha-carboxyl and alpha-amino groups of glutamate
      are conserved in the receptor, consistent with glutamate binding to the
      ligand-binding domain. Binding is retained but is antagonistic rather than
      the core activating function.
    action: KEEP_AS_NON_CORE
    reason: Glutamate binding is experimentally supported (glutamate competes
      with GABA), but at GrlE glutamate is an antagonist that inhibits the GABA
      response, so this is a secondary/modulatory feature rather than the core
      function.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: Glutamate acts as a competitive inhibitor of GABA
        functions in Dictyostelium
- term:
    id: GO:1901261
    label: regulation of sorocarp spore cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:16672332
  qualifier: acts_upstream_of_or_within
  review:
    summary: GABA acting through GrlE induces terminal differentiation and
      encapsulation of spore cells by triggering AcbA/SDF-2 release. This is a
      core developmental role of the receptor.
    action: ACCEPT
    reason: Directly supported by the disruption and induction phenotypes showing
      GrlE-dependent GABA control of prespore encapsulation.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: they rapidly encapsulate in response to the signalling
        peptide SDF-2
    - reference_id: PMID:16672332
      supporting_text: GABA induces the release of the precursor of SDF-2, AcbA,
        from prespore cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:16527814
  qualifier: is_active_in
  review:
    summary: GFP-tagged GrlE localizes to the plasma membrane, the expected
      location for a signal-transducing GPCR. Well supported by direct evidence.
    action: ACCEPT
    reason: Direct localization evidence places the receptor at the plasma
      membrane, where it is active in ligand sensing.
    supported_by:
    - reference_id: PMID:16527814
      supporting_text: DdmGluPR was localized to the plasma membrane of axenically
        grown Ax-2 cells expressed as a green fluorescent protein fusion protein
- term:
    id: GO:0004965
    label: G protein-coupled GABA receptor activity
  evidence_type: IMP
  original_reference_id: PMID:16672332
  qualifier: enables
  review:
    summary: Direct genetic evidence identifies GrlE as the GABA receptor in
      Dictyostelium (null cells fail to respond to GABA). This is the core
      molecular function.
    action: ACCEPT
    reason: Experimental (IMP) demonstration that GrlE mediates the cellular
      response to GABA supports this as the primary molecular function.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
        seven-transmembrane G-protein-coupled receptor that is most similar to
        GABA(B) receptors
- term:
    id: GO:0007214
    label: gamma-aminobutyric acid signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:16672332
  qualifier: acts_upstream_of_or_within
  review:
    summary: GrlE initiates a GABA signal transduction pathway (relayed via PI3
      kinase and PkbR1) that controls SDF-2 production and terminal
      differentiation. Core biological process for this gene.
    action: ACCEPT
    reason: Experimentally supported; GABA signaling through GrlE is the defining
      pathway in which the gene acts.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: The signal transduction pathway from GABA/GrlE appears to
        be mediated by PI3 kinase and the PKB-related protein kinase PkbR1
- term:
    id: GO:0008066
    label: glutamate receptor activity
  evidence_type: IMP
  original_reference_id: PMID:16672332
  qualifier: enables
  review:
    summary: GrlE was originally identified as a metabotropic glutamate
      receptor-like protein and binds glutamate, but functionally glutamate acts
      as a competitive inhibitor of the GABA response rather than as an
      activating agonist. The glutamate-responsive role is secondary to the core
      GABA receptor function.
    action: KEEP_AS_NON_CORE
    reason: Glutamate is a genuine ligand of GrlE but acts antagonistically to
      GABA; classifying GrlE primarily as a glutamate receptor overstates this
      modulatory role, so it is retained as non-core rather than as the core
      molecular function.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: Glutamate acts as a competitive inhibitor of GABA
        functions in Dictyostelium
- term:
    id: GO:0031152
    label: aggregation involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:16527814
  qualifier: acts_upstream_of_or_within
  review:
    summary: GrlE-null cells show delayed aggregate formation upon starvation,
      implicating the receptor in early developmental aggregation. This is a
      distinct early-development role from its late GABA/spore function.
    action: KEEP_AS_NON_CORE
    reason: Supported by the disruption phenotype, but this early aggregation
      role is a pleiotropic early-development function upstream of the receptor's
      core late GABA-mediated activity.
    supported_by:
    - reference_id: PMID:16527814
      supporting_text: DdmGluPR-null cells exhibited delayed aggregates formation
        upon starvation and impaired chemotaxis toward cAMP
- term:
    id: GO:0043327
    label: chemotaxis to cAMP
  evidence_type: IMP
  original_reference_id: PMID:16527814
  qualifier: acts_upstream_of_or_within
  review:
    summary: GrlE-null cells display impaired chemotaxis toward cAMP and altered
      induction of cAMP-signaling components (cAR1, aca), implicating the
      receptor in early cAMP-driven aggregation. A pleiotropic early-development
      role rather than the core function.
    action: KEEP_AS_NON_CORE
    reason: The chemotaxis phenotype is experimentally supported but reflects an
      indirect, early-development role of GrlE upstream of cAMP signaling, not
      its core GABA receptor activity.
    supported_by:
    - reference_id: PMID:16527814
      supporting_text: DdmGluPR-null cells exhibited delayed aggregates formation
        upon starvation and impaired chemotaxis toward cAMP
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16527814
  title: A metabotropic glutamate receptor family gene in Dictyostelium discoideum.
  findings:
  - statement: GrlE/DdmGluPR is a metabotropic glutamate receptor family GPCR that
      localizes to the plasma membrane.
    supporting_text: DdmGluPR was localized to the plasma membrane of axenically
      grown Ax-2 cells expressed as a green fluorescent protein fusion protein
  - statement: The alpha-carboxyl and alpha-amino glutamate-binding residues are
      conserved in GrlE, but the gamma-carboxyl-interacting residues are not.
    supporting_text: the residues of mGluRs involved in the binding of the
      alpha-carboxylic and alpha-amino groups of glutamate were well conserved in
      DdmGluPR
  - statement: GrlE-null cells grow faster to higher densities, aggregate late,
      and show impaired chemotaxis toward cAMP, implicating GrlE in early
      development.
    supporting_text: DdmGluPR-null cells exhibited delayed aggregates formation
      upon starvation and impaired chemotaxis toward cAMP
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified abstract (Taniura et al., J Biol Chem 2006).
      Establishes GrlE identity as an mGluR-family GPCR, plasma membrane
      localization, and the early-development/chemotaxis phenotype used for the
      localization and early-development annotations.
- id: PMID:16672332
  title: GABA induces terminal differentiation of Dictyostelium through a GABAB receptor.
  findings:
  - statement: GrlE is the seven-transmembrane GABA(B)-like receptor for GABA in
      Dictyostelium.
    supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
      seven-transmembrane G-protein-coupled receptor that is most similar to
      GABA(B) receptors
  - statement: GABA acting through GrlE induces release of the SDF-2 precursor
      AcbA from prespore cells to drive terminal spore differentiation.
    supporting_text: GABA induces the release of the precursor of SDF-2, AcbA,
      from prespore cells
  - statement: GABA/GrlE signaling is relayed through PI3 kinase and the
      PKB-related kinase PkbR1, and glutamate competitively inhibits it.
    supporting_text: The signal transduction pathway from GABA/GrlE appears to be
      mediated by PI3 kinase and the PKB-related protein kinase PkbR1
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified abstract (Anjard & Loomis, Development 2006).
      Directly identifies GrlE as the GABA receptor driving terminal
      differentiation and provides the core GABA receptor and GABA signaling
      annotations; glutamate is described as a competitive inhibitor.
suggested_questions:
- question: >-
    Which heterotrimeric G-protein alpha subunit does GrlE couple to when GABA
    triggers the PI3-kinase / PkbR1 relay that drives AcbA/SDF-2 release during
    culmination?
core_functions:
- description: GrlE is a plasma-membrane class C G-protein-coupled receptor that
    functions as the receptor for GABA in Dictyostelium, initiating a GABA
    signaling pathway that triggers AcbA/SDF-2 release and drives terminal
    differentiation and encapsulation of spore cells during culmination.
  molecular_function:
    id: GO:0004965
    label: G protein-coupled GABA receptor activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0007214
    label: gamma-aminobutyric acid signaling pathway
  supported_by:
  - reference_id: PMID:16672332
    supporting_text: The receptor for GABA in Dictyostelium, GrlE, is a
      seven-transmembrane G-protein-coupled receptor that is most similar to
      GABA(B) receptors
  - reference_id: PMID:16672332
    supporting_text: GABA induces the release of the precursor of SDF-2, AcbA,
      from prespore cells
  - reference_id: PMID:16527814
    supporting_text: DdmGluPR was localized to the plasma membrane of axenically
      grown Ax-2 cells expressed as a green fluorescent protein fusion protein