GHSR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001616 growth hormone secretagogue receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: Ghrelin receptor activity is the defining molecular function of GHSR and is correctly inherited by the horse receptor. Reason: PAINT placed this IBD at PTN002797666, the GHSR clade node (Euteleostomi), seeded by experimental rat, human and pig GHSR annotations. Horse F6QF00 sits in PANTHER subfamily PTHR24243:SF7 (GROWTH HORMONE SECRETAGOGUE RECEPTOR TYPE 1) with these donors, so it lies inside the inheriting clade. The horse sequence is full length and conserves every curated human ligand-contact residue and the C116-C198 disulfide. GHSR1a transcript is sequence-confirmed in horse pituitary. Equine chondrocytes show ghrelin responses through GHS-R1a that an antagonist blocks. Supporting Evidence: PMID:10604470 an endogenous ligand specific for GHS-R. PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. file:HORSE/GHSR/GHSR-bioinformatics/RESULTS-rereview.md Every curated human site in the record is conserved in horse PMID:29526750 ghrelin protects chondrocytes against LPS-induced damage via interaction with GHS-R1a file:HORSE/GHSR/GHSR-deep-research-falcon.md Equine GHSR1a RT-PCR products from pituitary and adrenal medulla have additionally been sequence-verified against the horse reference genome
GO:0001616 growth hormone secretagogue receptor activity	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara ortholog transfer of the human ghrelin receptor activity, consistent with the IBA row. Reason: The donor is human Q92847, which is in the same PANTHER subfamily (SF7) as horse F6QF00 and has experimental ghrelin receptor annotations and ghrelin-bound active structures. This row and the IBA row assert the same claim. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. file:HORSE/GHSR/GHSR-bioinformatics/RESULTS-rereview.md Every curated human site in the record is conserved in horse
GO:0004930 G protein-coupled receptor activity	IEA GO_REF:0000120	TOO GENERAL	Summary: Correct, but entailed by the more specific growth hormone secretagogue receptor activity. Reason: GO:0001616 is_a GO:0004930 (verified against the OLS ancestor list). GO:0001616 is accepted elsewhere in this review, so this generic GPCR term adds no information. GHSR is a genuine class A GPCR, so the claim itself is true. Supporting Evidence: PMID:8688086 A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R)
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: The ghrelin receptor acts at the plasma membrane. Reason: This IBD sits at the deeper peptide-receptor node PTN002797649, which includes motilin, neurotensin and neuromedin U receptors as well as GHSR. Plasma-membrane localization of the active receptor is ancestral to that clade. The horse protein keeps all seven transmembrane helices and the extracellular N-glycosylation sites. Supporting Evidence: PMID:8688086 A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: The ghrelin receptor is located in the plasma membrane; consistent with the IBA row. Reason: Combined automated transfer that agrees with the IBA plasma-membrane assertion and with the seven-transmembrane topology conserved in horse. Supporting Evidence: PMID:8688086 A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R)
GO:0007154 cell communication	IEA GO_REF:0000117	TOO GENERAL	Summary: True but uninformative; entailed by the accepted GPCR signaling pathway term. Reason: GO:0007186 G protein-coupled receptor signaling pathway is_a GO:0007154 cell communication (OLS ancestors). GO:0007186 and GO:0009755 are accepted here, so this ARBA-derived root-level process adds nothing. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0007165 signal transduction	IEA GO_REF:0000104	TOO GENERAL	Summary: True but uninformative; entailed by the accepted GPCR signaling pathway term. Reason: GO:0007186 is_a GO:0007165 (OLS ancestors). The specific GPCR and hormone-mediated signaling terms accepted in this review already entail signal transduction. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0007186 G protein-coupled receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: Ghrelin binding activates heterotrimeric G-protein signaling; this is the core process. Reason: GPCR signaling is ancestral to the peptide-receptor node PTN002797649. For GHSR specifically, cryo-EM structures capture the ghrelin-bound receptor coupled to G protein. The horse receptor conserves the ERY, CWxP and NPxxY activation motifs at the human positions. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. file:HORSE/GHSR/GHSR-bioinformatics/RESULTS-rereview.md The class A GPCR motifs are at identical positions in both
GO:0007186 G protein-coupled receptor signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: Same claim as the IBA GPCR signaling row. Reason: Combined automated transfer that agrees with the IBA row and with the conserved receptor architecture. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0007612 learning	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: An organism-level behavioural readout. The cellular mechanism is captured by regulation of synaptic plasticity. Reason: The mouse donor evidence places GHSR as a coreceptor with DRD1 in hippocampal neurons, where it redirects DRD1 to Gq signaling and so initiates synaptic plasticity. Learning is the downstream behavioural outcome measured in animals. GHSR does molecular work at the level of the receptor heteromer and synaptic plasticity, and those claims are kept in GO:0015026 and GO:0048167. A behavioural term on top of them is an over-annotation from a phenotype readout. It has also not been examined in horse. Supporting Evidence: file:human/GHSR/GHSR-uniprot.txt Following DRD1 activation by dopamine in hippocampal neurons, GHSR acts as a coreceptor, resulting in DRD1 coupling to G(q) at the expense of G(s), initiating hippocampal synaptic plasticity involved in memory and learning
GO:0007613 memory	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: An organism-level behavioural readout. The cellular mechanism is captured by regulation of synaptic plasticity. Reason: Same basis as the learning row. Memory is the behavioural consequence of GHSR-DRD1 heteromer signaling in hippocampal neurons, which is captured more directly by coreceptor activity and regulation of synaptic plasticity. Supporting Evidence: file:human/GHSR/GHSR-uniprot.txt Following DRD1 activation by dopamine in hippocampal neurons, GHSR acts as a coreceptor, resulting in DRD1 coupling to G(q) at the expense of G(s), initiating hippocampal synaptic plasticity involved in memory and learning
GO:0008154 actin polymerization or depolymerization	IEA GO_REF:0000107	UNDECIDED	Summary: Transferred from a human immune-cell IDA whose actin data are not in the available abstract. Reason: The donor annotation is a human IDA from Dixit et al. 2004. Only the abstract is cached, and it does not describe the actin or cytoskeletal experiment. Whether GHSR participates directly in actin remodeling, rather than ghrelin signaling having downstream cytoskeletal effects, cannot be judged without the full text. This is an organism-independent problem; there is also no horse immune-cell evidence. Supporting Evidence: PMID:15232612 GHS-R and ghrelin are expressed in human T lymphocytes and monocytes
GO:0008343 adult feeding behavior	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ghrelin-induced feeding is a canonical physiological output of GHSR signaling; non-core. Reason: Ghrelin stimulates appetite through GHSR in mammals, and GHSR loss-of-function variants show that the receptor mediates the hormone's endocrine and appetite effects. Feeding behaviour is an organismal outcome of receptor signaling in hypothalamic neurons, not a molecular activity of GHSR itself. It is therefore kept as non-core. No equine feeding experiment links receptor activity to intake, although equine plasma ghrelin falls after feeding. Supporting Evidence: PMID:16511605 its endogenous ligand--ghrelin--stimulates, through the GHSR, GH secretion and appetite
GO:0009725 response to hormone	IEA GO_REF:0000107	TOO GENERAL	Summary: True but entailed by the accepted hormone-mediated signaling pathway term. Reason: GO:0009755 hormone-mediated signaling pathway is_a GO:0032870 cellular response to hormone stimulus, which is_a GO:0009725 response to hormone (OLS ancestors). GO:0009755 is accepted here for the same receptor, so this term adds nothing. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0009755 hormone-mediated signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: GHSR transduces the peptide hormone ghrelin; core process. Reason: The IBD is at the GHSR clade node PTN002797666, seeded by human and pig GHSR, and horse SF7 GHSR is a descendant. Ghrelin is a circulating stomach hormone, and GHSR is its signaling receptor. The human GO-CAM for the ghrelin-GHSR pair (gomodel:67f85f2b00000823) models GHSR in this process. Supporting Evidence: PMID:10604470 an endogenous ligand specific for GHS-R. PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0009755 hormone-mediated signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: Same claim as the IBA hormone-mediated signaling row. Reason: This is an ortholog transfer from human Q92847 that agrees with the IBA row. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0009986 cell surface	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Consistent with a cell-surface receptor; the plasma membrane term is the primary location. Reason: A GPCR with an extracellular ligand-binding pocket is exposed at the cell surface, so the term is correct. Plasma membrane, accepted above, is the primary location for core_functions. Cell surface is not an is_a parent of plasma membrane, so it is kept as a compatible secondary location rather than marked as redundant. Supporting Evidence: PMID:8688086 A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R)
GO:0015026 coreceptor activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR acts as a ligand-independent coreceptor for dopamine receptors in neurons; a genuine but context-specific activity. Reason: Rodent experiments show GHSR forming heteromers with DRD1 and DRD2 in which it changes dopamine receptor G-protein coupling. The human GO-CAMs gomodel:69c59f8a00000139 and gomodel:69c59f8a00001474 model GHSR with this coreceptor activity. The activity is neuron-specific and independent of ghrelin, so it is retained as non-core. The ortholog transfer comes from mouse Q99P50, a member of the same SF7 subfamily, and the residues known to matter are conserved. Heteromerization has not been tested for the equine receptor. Supporting Evidence: file:human/GHSR/GHSR-uniprot.txt Following DRD1 activation by dopamine in hippocampal neurons, GHSR acts as a coreceptor
GO:0016020 membrane	IEA GO_REF:0000002	MODIFY	Summary: Correct but less specific than the supported plasma membrane location. Reason: The InterPro-derived term is accurate but generic. The receptor's specific location, plasma membrane, is already supported for this gene by IBA, and that term should be used. Proposed replacements: plasma membrane Supporting Evidence: PMID:8688086 A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R)
GO:0016520 growth hormone-releasing hormone receptor activity	IEA GO_REF:0000107	MODIFY	Summary: The ligand is wrong. GHSR binds ghrelin, not growth hormone-releasing hormone (GHRH); the GHRH receptor is GHRHR. Reason: The GO:0016520 definition (OLS) is "Combining with growth hormone-releasing hormone to initiate a change in cell activity". GO:0001616 is defined as combining with ghrelin. The ghrelin discovery paper explicitly separates the GHSR pathway from GHRH regulation. The intended function, a receptor for a GH-releasing ligand, is right, but the ligand is not. The defect is on the human donor IDA rows, which cite ghrelin and secretagogue studies, and the human GO-CAM gomodel:67f85f2b00000823 carries the same GHRH term. Replace with the ghrelin receptor term. Proposed replacements: growth hormone secretagogue receptor activity Supporting Evidence: PMID:10604470 there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH).
GO:0023052 signaling	IEA GO_REF:0000117	TOO GENERAL	Summary: True but uninformative; entailed by the accepted GPCR signaling pathway term. Reason: GO:0007186 is_a GO:0023052 (OLS ancestors). This ARBA-derived root-level term adds nothing to the specific signaling terms accepted here. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0032100 positive regulation of appetite	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ghrelin-GHSR signaling promotes appetite; a well-established physiological role, non-core. Reason: Ghrelin is the best-known orexigenic hormone, and the effect requires GHSR. The role is physiologically important, but it is an organism-level regulatory outcome of receptor signaling in hypothalamic circuits. It is therefore kept as non-core next to the receptor activity and signaling core. Supporting Evidence: PMID:16511605 its endogenous ligand--ghrelin--stimulates, through the GHSR, GH secretion and appetite
GO:0032691 negative regulation of interleukin-1 beta production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR-mediated suppression of IL-1beta in human immune cells; context-specific, non-core. Reason: The human study shows that ghrelin acts via GHS-R on monocytes and T cells to inhibit proinflammatory cytokine expression. It is a tissue-specific downstream consequence of receptor signaling. The ortholog transfer is within SF7. In horse, ghrelin acting via GHS-R1a protects chondrocytes from LPS damage, which fits an anti-inflammatory signaling role, but equine cytokine output was not measured. Supporting Evidence: PMID:15232612 ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha.
GO:0032715 negative regulation of interleukin-6 production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR-mediated suppression of IL-6 in human immune cells; context-specific, non-core. Reason: Same human immune-cell evidence as the IL-1beta row. This is a downstream signaling consequence in leukocytes and is not part of the defining receptor function. Supporting Evidence: PMID:15232612 ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha.
GO:0032720 negative regulation of tumor necrosis factor production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR-mediated suppression of TNF in human immune cells; context-specific, non-core. Reason: Same human immune-cell evidence as the IL-1beta row; kept as a non-core downstream consequence of receptor signaling. Supporting Evidence: PMID:15232612 ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha.
GO:0038023 signaling receptor activity	IEA GO_REF:0000117	TOO GENERAL	Summary: True but entailed by the accepted growth hormone secretagogue receptor activity. Reason: GO:0001616 is_a GO:0038023 through G protein-coupled receptor activity and transmembrane signaling receptor activity (OLS ancestors). GO:0001616 is accepted here, so this ARBA-derived generic term adds nothing. Supporting Evidence: PMID:35027551 active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin.
GO:0040018 positive regulation of multicellular organism growth	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR signaling, including its constitutive activity, supports growth through GH release; non-core. Reason: The human donor IMP comes from a familial short stature variant that removes constitutive GHSR activity but keeps the ghrelin response. This links receptor activity to growth through pituitary GH secretion. Growth is an organismal outcome, so the term is non-core. GHSR1a is sequence-confirmed in horse pituitary, but equine growth effects have not been measured. Supporting Evidence: PMID:16511605 selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin. PMID:42426797 Sequencing confirmed both products were identical to the equine GHSR1a reference sequence
GO:0043005 neuron projection	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal-process localization fits the receptor's neuronal roles; non-core location. Reason: GHSR is expressed in hypothalamic and hippocampal neurons, where it signals and heteromerizes with dopamine receptors, so a neuron-projection location is plausible. It is a cell-type-specific location and not the general receptor compartment. Supporting Evidence: file:human/GHSR/GHSR-uniprot.txt Following DRD1 activation by dopamine in hippocampal neurons, GHSR acts as a coreceptor
GO:0045121 membrane raft	IEA GO_REF:0000107	UNDECIDED	Summary: Transferred from a human immune-cell IDA whose raft data are not in the available abstract. Reason: The donor is a human IDA from Dixit et al. 2004. The cached abstract does not describe the membrane-raft experiment, so the localization cannot be checked here. Raft partitioning may also depend on cell type and activation state, and no horse data exist. Supporting Evidence: PMID:15232612 GHS-R and ghrelin are expressed in human T lymphocytes and monocytes
GO:0046697 decidualization	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: A human endometrial ligand-supplementation finding transferred to a species without a comparable decidual reaction. Reason: The human donor evidence comes from adding ghrelin to endometrial stromal cultures, which raises decidualization markers. That shows the receptor pathway can modulate the process, not that GHSR does a step of decidualization, so even the human IDA is a regulatory effect at most. For horse, the transfer is also biologically doubtful: equids form an epitheliochorial placenta and lack the invasive stromal decidual reaction of human pregnancy. The term should not be carried to F6QF00 without equine uterine evidence. Supporting Evidence: PMID:17494105 Ghrelin administered in combination with sex steroids to HESC, resulted in an increase in PRL and IGFBP-1 production
GO:0048167 regulation of synaptic plasticity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR-DRD1 heteromer signaling initiates hippocampal synaptic plasticity; non-core. Reason: In rodent hippocampal neurons, GHSR acts as a coreceptor that switches DRD1 to Gq signaling and so initiates synaptic plasticity. The receptor does mechanistic work in this regulation, but the role is neuron-specific and ligand-independent, so it is kept as non-core. Supporting Evidence: file:human/GHSR/GHSR-uniprot.txt Following DRD1 activation by dopamine in hippocampal neurons, GHSR acts as a coreceptor, resulting in DRD1 coupling to G(q) at the expense of G(s), initiating hippocampal synaptic plasticity
GO:0050728 negative regulation of inflammatory response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR-mediated anti-inflammatory signaling; supported in human leukocytes and fitting the equine chondrocyte data; non-core. Reason: Human monocytes and T cells show GHSR-dependent inhibition of proinflammatory cytokines. In horse, the protective effect of ghrelin on LPS-challenged chondrocytes depends on GHS-R1a. Low ghrelin concentrations and des-acyl ghrelin were damaging in that study, so the effect is not uniformly anti-inflammatory. The term is kept as a context-dependent, non-core role. Supporting Evidence: PMID:15232612 ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. PMID:29526750 ghrelin protects chondrocytes against LPS-induced damage via interaction with GHS-R1a
GO:2000292 regulation of defecation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GHSR acts as a coreceptor with DRD2 in lumbosacral defecation centres; non-core. Reason: Rodent work shows a GHSR-DRD2 coreceptor mechanism in spinal defecation centres, captured in the human GO-CAM gomodel:69c59f8a00001474. GHSR changes DRD2 coupling there, which is mechanistic work in the regulation. The context is neuron-specific, so the term is non-core. Supporting Evidence: file:human/GHSR/GHSR-uniprot.txt Following DRD2 activation by dopamine in lumbosacral defecation centers, GHSR acts as a coreceptor

Gene Description

Existing Annotations Review

Core Functions

Plasma-membrane receptor for acyl-ghrelin and synthetic growth hormone secretagogues that activates heterotrimeric G-protein (mainly Gq/11) signaling and so transduces the stomach-derived hormone signal.

References

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Protnlm Function Review

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