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.
| 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. Proposed replacements: G protein-coupled GABA receptor activity 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 |
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Download this section (compressed HTML)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?
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