NTSR1 encodes neurotensin receptor type 1 (NTS1), a 418-residue class A seven-transmembrane G protein-coupled receptor and the high-affinity receptor for the tridecapeptide neurotensin. It is displayed at the plasma membrane - in neurons predominantly along extrasynaptic somatodendritic membranes, with smaller axonal and presynaptic pools, and in epithelial and tumour cells within palmitoylation-dependent, caveolin-enriched membrane rafts. Agonist binding by the extracellular loops and the outer transmembrane pocket switches the receptor into a conformation that acts as a guanine-nucleotide exchange factor for heterotrimeric G proteins: canonically Gq/11, activating phospholipase C to generate inositol trisphosphate and diacylglycerol and to mobilize stored calcium, and, because the receptor couples promiscuously, also Gi/o and other classes. Downstream signaling activates ERK and Akt, protects cells from apoptosis, and in colonic epithelium drives NF-kB-dependent miRNA and gene-expression programs. Receptor phosphorylation recruits beta-arrestin, which desensitizes and internalizes the receptor and constitutes a signaling arm separable from the G protein arm. Dual palmitoylation at Cys381/Cys383 is required for raft residence and efficient Gq/11 coupling, and the receptor homodimerizes concentration-dependently, which modulates but does not enable G protein activation. Physiologically, neurotensin signaling through this receptor lowers body temperature and blood pressure, suppresses feeding, modulates locomotion, dopaminergic transmission and inhibitory synaptic transmission in limbic circuits, and participates in reward-related behaviour; in colon and breast cancers the receptor supports proliferative and pro-survival signaling. The paralogous NTSR2, not NTSR1, mediates neurotensin's effects on thermal nociception.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001659 temperature homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 mediates the hypothermic action of central neurotensin: NTSR1-null mice are hyperthermic and no longer lower body temperature in response to i.c.v. neurotensin. Reason: The claim is well supported by rodent genetics, so it is kept, but it is an organismal homeostatic outcome of neurotensin receptor signaling in thermoregulatory circuits rather than the receptor's core molecular role. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:12384239 hyperthermic; their body temperature was not affected by intracerebroventricular PMID:12384239 clearly implicated in thermal and feeding regulation, weight control, and |
| GO:0003085 negative regulation of systemic arterial blood pressure | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin acting at NTSR1 lowers systemic arterial blood pressure; cardiovascular effects are a recognized consequence of NTSR1 activation. Reason: Blood-pressure regulation is a downstream physiological role listed among NTSR1's recognized functions ('involved in the regulation of blood pressure, body temperature, weight and the response to pain'), not the receptor's core activity, so it is retained as non-core. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:31243364 engages multiple subtypes of G protein |
| GO:0003254 regulation of membrane depolarization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 on midbrain dopaminergic and other neurons depolarizes the postsynaptic membrane after neurotensin binding, consistent with its Gq/PLC/calcium signaling and somatodendritic localization. Reason: Changing membrane excitability is a genuine but downstream consequence of NTSR1 signaling in neurons, and is mediated by effector channels rather than by the receptor itself; kept as non-core. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: NTSR1 is a class A seven-transmembrane G protein-coupled receptor, so generic GPCR activity is true of it; the specific ligand-defined activity is GO:0016492. Reason: The claim is correct (InterPro IPR000276 (rhodopsin-like GPCR) mapping), but GO:0016492 G protein-coupled neurotensin receptor activity is asserted and accepted elsewhere in this review and entails GPCR activity, so the parent term adds nothing; the row is not wrong, merely uninformative. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:8381365 Cloning and expression of a complementary DNA encoding a hig... | TOO GENERAL | Summary: NTSR1 is a class A seven-transmembrane G protein-coupled receptor, so generic GPCR activity is true of it; the specific ligand-defined activity is GO:0016492. Reason: The claim is correct (author statement in the cloning paper), but GO:0016492 G protein-coupled neurotensin receptor activity is asserted and accepted elsewhere in this review and entails GPCR activity, so the parent term adds nothing; the row is not wrong, merely uninformative. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin |
| GO:0005515 protein binding | IPI PMID:17620610 Dimerization of the class A G protein-coupled neurotensin re... | MODIFY | Summary: IPI row recording the NTSR1-neurotensin interaction characterized in purified receptor preparations, where agonist binding shows Hill slopes of ~1 (monomer) and ~2 (dimer). Reason: Bare protein binding carries no functional information, but this interaction is exactly the receptor's ligand-recognition activity, which the cited paper measures directly (agonist neurotensin binding plus Gq activation by the monomer). Replace with the informative molecular function GO:0016492, which NTSR1 already carries by IDA, IMP and IBA; removal is not appropriate because a specific replacement is evidence-backed here. Proposed replacements: G protein-coupled neurotensin receptor activity Supporting Evidence: PMID:17620610 binds the agonist neurotensin with a PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers Reactome:R-HSA-388900 The neurotensin receptor binds neurotensin. |
| GO:0005515 protein binding | IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... | REMOVE | Summary: IPI row for the mature neurotensin peptide (PRO_0000019524 of P30990), attributed to an FGFR allosteric-inhibitor paper. Reason: Bare GO:0005515 protein binding is uninformative and is slated for do-not-annotate; removing it does not dispute the reported NTSR1-neurotensin interaction, which is captured informatively by GO:0016492 (accepted elsewhere in this review). The cached record for the cited reference is abstract-only and its abstract concerns FGFR pharmacology, so no more specific molecular function can be substituted from it; the removal rests on the generic-term policy, not on any claim that the interaction record is wrong. Supporting Evidence: Reactome:R-HSA-388900 The neurotensin receptor binds neurotensin. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI row for an NTSR1-RAMP3 interaction detected in the BioPlex 3.0 proteome-scale affinity-purification mass spectrometry network. Reason: Bare protein binding is uninformative. A high-throughput AP-MS association with RAMP3 does not specify a molecular function for NTSR1, and the cached text reports only the network as a whole (the NTSR1-specific pair is in supplementary data), so no evidence-backed specific replacement term is available. Removal reflects the uninformativeness of the term, not disbelief in the interaction. Supporting Evidence: PMID:33961781 of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: IPI row for an NTSR1-RAMP1 (O60894) complex detected in a multiplexed suspension-bead-array screen of 215 GPCRs against the three RAMPs. Reason: Bare protein binding is uninformative, and a RAMP association does not by itself establish a molecular function or a receptor-activity change for NTSR1; the screen reports GPCR-RAMP pairs at scale, with the NTSR1-specific values in supplementary tables rather than in the cached text. Removal follows the generic-protein-binding policy; it is not a judgment that the interaction is false, and a RAMP-dependent pharmacology or trafficking effect would be worth annotating if demonstrated for NTSR1 specifically. Supporting Evidence: PMID:39083597 122 GPCRs that showed strong evidence for interaction with at least one RAMP |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: IPI row for an NTSR1-RAMP3 (O60896) complex detected in a multiplexed suspension-bead-array screen of 215 GPCRs against the three RAMPs. Reason: Bare protein binding is uninformative, and a RAMP association does not by itself establish a molecular function or a receptor-activity change for NTSR1; the screen reports GPCR-RAMP pairs at scale, with the NTSR1-specific values in supplementary tables rather than in the cached text. Removal follows the generic-protein-binding policy; it is not a judgment that the interaction is false, and a RAMP-dependent pharmacology or trafficking effect would be worth annotating if demonstrated for NTSR1 specifically. Supporting Evidence: PMID:39083597 122 GPCRs that showed strong evidence for interaction with at least one RAMP |
| GO:0005783 endoplasmic reticulum | TAS PMID:9763490 Correlative ultrastructural distribution of neurotensin rece... | KEEP AS NON CORE | Summary: Immunogold EM of rat substantia nigra localizes a substantial intracellular pool of high-affinity neurotensin receptor to smooth ER membranes, interpreted as newly synthesized receptor. Reason: The localization is real but biosynthetic: the ER pool is receptor en route to the surface, and the authors note these intracellular receptors already bind ligand. The receptor's site of action is the plasma membrane (accepted elsewhere), so the ER is kept as a non-core location rather than accepted as a core one. Supporting Evidence: PMID:9763490 membranes of smooth endoplasmic reticulum and Golgi apparatus PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0005794 Golgi apparatus | TAS PMID:9763490 Correlative ultrastructural distribution of neurotensin rece... | KEEP AS NON CORE | Summary: The same ultrastructural study finds intracellular receptor over Golgi membranes in comparable proportion to the ER pool. Reason: As for the ER row: a genuine biosynthetic/trafficking location rather than the site at which the receptor executes its function, so it is retained as non-core. Supporting Evidence: PMID:9763490 membranes of smooth endoplasmic reticulum and Golgi apparatus |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBD-based phylogenetic inference placing the neurotensin/peptide-receptor clade's activity at the plasma membrane, with the human gene itself among the descendant evidences. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. The IBA reflects a curator's judgement that plasma-membrane activity arose at an ancestral node of this receptor family, which is uncontroversial for a 7TM peptide receptor; NTSR1's own presence in the WITH/FROM list marks experimental grounding on the target itself. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons PMID:42870023 Full-length human NTSR1 was expressed and purified as previously described |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based curation (GO_REF:0000052) localizing NTSR1 to the plasma membrane. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Cell membrane {ECO:0000269|PubMed:8381365} PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (SL-0039 cell membrane) for NTSR1. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Cell membrane {ECO:0000269|PubMed:8381365} |
| GO:0005886 plasma membrane | IMP PMID:8381365 Cloning and expression of a complementary DNA encoding a hig... | ACCEPT | Summary: Expression of the cloned human NTSR1 cDNA in COS cells reconstitutes high-affinity cell-surface neurotensin binding and signaling. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains file:human/NTSR1/NTSR1-uniprot.txt Cell membrane {ECO:0000269|PubMed:8381365} |
| GO:0005886 plasma membrane | TAS PMID:8381365 Cloning and expression of a complementary DNA encoding a hig... | ACCEPT | Summary: Author statement, in the human cloning paper, that NTSR1 is a cell-surface seven-transmembrane receptor. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Reactome places NTSR1 at the plasma membrane as a liganded Gq/11-activating GPCR in the neurotensin signaling reactions. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: Reactome:R-HSA-379048 Liganded Gq/11-activating GPCRs act as GEFs for Gq/11 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-388900 | ACCEPT | Summary: Reactome places NTSR1 at the plasma membrane as a liganded Gq/11-activating GPCR in the neurotensin signaling reactions. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: Reactome:R-HSA-388900 The neurotensin receptor binds neurotensin. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Reactome places NTSR1 at the plasma membrane as a liganded Gq/11-activating GPCR in the neurotensin signaling reactions. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Cell membrane {ECO:0000269|PubMed:8381365} |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Reactome places NTSR1 at the plasma membrane as a liganded Gq/11-activating GPCR in the neurotensin signaling reactions. Reason: The plasma membrane is where NTSR1 acts: it is a multi-pass membrane receptor that binds extracellular neurotensin and acts as a GEF for heterotrimeric G proteins on the cytoplasmic face. UniProt records cell membrane localization, the ultrastructural study finds receptor along somatodendritic plasma membranes, and the purified human receptor couples to Gi and Gq heterotrimers. This is a core location. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Cell membrane {ECO:0000269|PubMed:8381365} |
| GO:0006171 cAMP biosynthetic process | IEA GO_REF:0000107 | MODIFY | Summary: Transfer of a rodent annotation implicating NTSR1 in cAMP production; NTSR1 is a promiscuous receptor that engages several G protein classes, including adenylate-cyclase-coupled ones, in addition to its canonical Gq/11 coupling. Reason: NTSR1 does not synthesize cAMP; adenylate cyclase does. What the receptor does is couple to G proteins that change cyclase activity, which is what GO:0007189 states for a receptor. Promiscuous G protein coupling by NTSR1 is well documented (structures with Gi1, 'engages multiple subtypes of G protein', and its use as the benchmark promiscuous GPCR in G protein selectivity assays), so the essence of the annotation is sound but the term type is wrong for a receptor. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:31243364 engages multiple subtypes of G protein PMID:31243364 present structures of human NTSR1 in complex with the agonist JMV449 and the PMID:38326620 by CaSR were compared against G-protein subtype activation by NTSR1, a promiscuous GPCR that PMID:42870023 which couple promiscuously in vitro |
| GO:0006950 response to stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Very broad 'response to stress' row transferred from rat Ntsr1. Reason: Neurotensin signaling is engaged in stress-related circuits, but 'response to stress' applied to the receptor is uninformative and far broader than any demonstrated NTSR1 function; no specific stress response has been shown to require the receptor's activity in a way this term would capture. It is not flatly false, so it is flagged as an over-annotation rather than removed. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:21725197 reduced ability to protect HEK293T cells against apoptosis induced by serum |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | TOO GENERAL | Summary: NTSR1 signals through heterotrimeric G proteins, so the generic GPCR signaling pathway term is true; the specific pathway terms asserted in this review are more informative. Reason: Correct (InterPro-based mapping) but subsumed: GO:0007218 neuropeptide signaling pathway is accepted elsewhere in this review, and GO:0007200 is proposed as a NEW annotation; both are descendants of GO:0007186, which therefore adds no information. The claim itself is not in doubt. Supporting Evidence: PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:8381365 Cloning and expression of a complementary DNA encoding a hig... | TOO GENERAL | Summary: NTSR1 signals through heterotrimeric G proteins, so the generic GPCR signaling pathway term is true; the specific pathway terms asserted in this review are more informative. Reason: Correct (author statement in the cloning paper) but subsumed: GO:0007218 neuropeptide signaling pathway is accepted elsewhere in this review, and GO:0007200 is proposed as a NEW annotation; both are descendants of GO:0007186, which therefore adds no information. The claim itself is not in doubt. Supporting Evidence: PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBD inference that neuropeptide signaling is the ancestral function of this receptor clade, with human NTSR1 itself among the descendant evidences. Reason: This is the core process for NTSR1: the receptor is the entry point of a neuropeptide (neurotensin) signaling pathway, binding the tridecapeptide at the cell surface and activating heterotrimeric G proteins. The purified human receptor activates Gq and Gi heterotrimers directly, and receptor-dependent signaling to ERK and to NF-kB/miRNA outputs is documented in human cells. The node placement is sound for a neurotensin receptor; the presence of NTSR1 in the WITH/FROM list indicates experimental grounding on the target itself and that the function is inherited rather than lineage-specific. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0007218 neuropeptide signaling pathway | IDA PMID:21725197 Neurotensin receptor-1 inducible palmitoylation is required ... | ACCEPT | Summary: Direct assay evidence that neurotensin stimulation of NTSR1 activates receptor-proximal signaling (Gq/11 coupling and ERK phosphorylation) in cells expressing the human receptor. Reason: This is the core process for NTSR1: the receptor is the entry point of a neuropeptide (neurotensin) signaling pathway, binding the tridecapeptide at the cell surface and activating heterotrimeric G proteins. The purified human receptor activates Gq and Gi heterotrimers directly, and receptor-dependent signaling to ERK and to NF-kB/miRNA outputs is documented in human cells. Supporting Evidence: PMID:21725197 mutant failed to interact with GΞ± q/11 following 15 min stimulation with 1 Β΅M NTS PMID:21725197 only WT-NTSR-1 efficiently stimulated ERK phosphorylation file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin |
| GO:0007218 neuropeptide signaling pathway | IGI PMID:21806946 Neurotensin signaling activates microRNAs-21 and -155 and Ak... | ACCEPT | Summary: Genetic-interaction evidence with the ligand NTS (P30990): neurotensin acting through NTSR1 in human colonic epithelial cells drives a defined downstream program. Reason: This is the core process for NTSR1: the receptor is the entry point of a neuropeptide (neurotensin) signaling pathway, binding the tridecapeptide at the cell surface and activating heterotrimeric G proteins. The purified human receptor activates Gq and Gi heterotrimers directly, and receptor-dependent signaling to ERK and to NF-kB/miRNA outputs is documented in human cells. The IGI with the cognate ligand is the canonical way to record a ligand-receptor pathway pair, and the experiments manipulate both the ligand and receptor expression. Supporting Evidence: PMID:21806946 Here, we used microRNA microarray expression analysis to detect the miRNA signature of NTR1 activation in human colonic NCM460 epithelial cells overexpressing NTR1. PMID:21806946 NTR1 activation stimulates expression of miR-21 and miR-155 in |
| GO:0007268 chemical synaptic transmission | TAS PMID:9763490 Correlative ultrastructural distribution of neurotensin rece... | MODIFY | Summary: TAS row from the ultrastructural study, which in fact reports that plasma-membrane neurotensin receptors are predominantly extrasynaptic. Reason: NTSR1 is not part of the machinery of neurotransmitter release and postsynaptic reception; the cited study explicitly describes the receptor distribution along somatodendritic membranes as homogeneous and 'predominantly extrasynaptic'. What neurotensin receptor signaling does is tune synaptic strength, which is what GO:0050804 states; NTSR1-selective pharmacology changes GABAergic transmission in extended amygdala, and rodent data show modulation of glutamate and GABA release. The essence is sound, the term is the wrong one. Proposed replacements: modulation of chemical synaptic transmission Supporting Evidence: PMID:9763490 predominantly extrasynaptic PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons PMID:42146540 suggesting that NTSR1 modulates presynaptic GABA input from local interneurons or afferent projections |
| GO:0007612 learning | IEA GO_REF:0000107 | TOO GENERAL | Summary: Broad 'learning' row transferred from rat Ntsr1, alongside the more specific associative-learning row. Reason: The claim is not in doubt, but GO:0008306 associative learning is a descendant of GO:0007612 and is kept in this review, so the parent term adds nothing. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:12384239 clearly implicated in thermal and feeding regulation, weight control, and |
| GO:0008306 associative learning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin signaling through NTSR1 modulates associative learning and conditioned behaviours in rodents. Reason: A plausible and curator-supported rodent behavioural role, consistent with NTSR1's documented effects on reward-related conditioning, but a circuit-level organismal process rather than a core receptor function. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:32470395 selectively antagonizing G protein signaling |
| GO:0009898 cytoplasmic side of plasma membrane | IEA GO_REF:0000107 | MODIFY | Summary: Row placing NTSR1 on the cytoplasmic side of the plasma membrane. Reason: NTSR1 is a seven-transmembrane, multi-pass integral membrane protein: its ligand pocket faces the extracellular space while only its loops and C-terminal tail are cytoplasmic, so restricting its location to the cytoplasmic leaflet is a contorted and partly misleading placement. The sound part of the claim is plasma-membrane localization, already accepted in this review; generalize to that term. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Proposed replacements: plasma membrane Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains file:human/NTSR1/NTSR1-uniprot.txt Multi-pass membrane protein |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: NTSR1 is displayed at the cell surface, where it binds extracellular neurotensin. Reason: Cell-surface display is directly demonstrated for the human receptor: transfection of the cloned cDNA yields cells with high-affinity neurotensin binding, and in neurons receptor immunoreactivity lines the somatodendritic plasma membrane where it is accessible to exogenous ligand. The term is accurate and complements the plasma-membrane annotations. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0010628 positive regulation of gene expression | IGI PMID:21806946 Neurotensin signaling activates microRNAs-21 and -155 and Ak... | KEEP AS NON CORE | Summary: Activation of NTSR1 by neurotensin in human colonocytes up-regulates miR-21 and miR-155 through NF-kB, changing expression of PTEN, SOCS1 and PPP2CA. Reason: The claim is directly supported in human cells, and the acts_upstream_of relation correctly expresses that the receptor is upstream of the transcriptional changes rather than executing them. It is a downstream consequence of receptor signaling, not the receptor's core function, so it is kept as non-core. Supporting Evidence: PMID:21806946 NTR1 activation stimulates expression of miR-21 and miR-155 in PMID:21806946 NT altered the expression levels of 38 miRNAs (8 up-regulated and 30 down-regulated) PMID:21806946 Here, we used microRNA microarray expression analysis to detect the miRNA signature of NTR1 activation in human colonic NCM460 epithelial cells overexpressing NTR1. |
| GO:0014049 positive regulation of glutamate secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin acting at NTSR1 increases glutamate release in rodent circuits. Reason: Presynaptic and circuit-level modulation of glutamate release is a recognized consequence of NTSR1 signaling and the receptor is present on axons as well as somata and dendrites; the actual secretion is performed by the presynaptic release machinery, so this is retained as a non-core, modulatory role. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 modest localization in myelinated and unmyelinated axons and astrocytic |
| GO:0014054 positive regulation of gamma-aminobutyric acid secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin acting at NTSR1 increases GABA release; NTSR1-selective pharmacology changes GABAergic transmission in the extended amygdala. Reason: Same reasoning as the glutamate-secretion row: a real modulatory role supported by NTSR1-selective pharmacology in mouse extended amygdala, but the receptor regulates rather than performs secretion. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:42146540 suggesting that NTSR1 modulates presynaptic GABA input from local interneurons or afferent projections PMID:42146540 SBI-553 reduces palatable food consumption in both fed and food-deprived |
| GO:0016020 membrane | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro-based 'membrane' row for a 7TM receptor. Reason: True but subsumed by GO:0005886 plasma membrane, which is accepted as the core location in this review; the generic parent adds no information. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains file:human/NTSR1/NTSR1-uniprot.txt Multi-pass membrane protein |
| GO:0016492 G protein-coupled neurotensin receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBD inference assigning G protein-coupled neurotensin receptor activity to this clade, with mouse Ntsr1 and human NTSR1 among the descendant evidences. Reason: This is NTSR1's core molecular function. UniProt types it as the receptor for the tridecapeptide neurotensin; the purified human receptor binds the agonist and catalyses nucleotide exchange on Gq heterotrimers, and smFRET of human NTSR1-Gi ternary complexes shows agonist-dependent opening of the Galphai helical domain correlating with GTP turnover. Ligand-defined receptor activity of exactly this kind is what GO:0016492 states. The ancestral node placement is well grounded, and human NTSR1's appearance in the WITH/FROM list reflects its own experimental annotation feeding the IBD rather than any circularity. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin PMID:17620610 binds the agonist neurotensin with a PMID:42870023 a pattern that also applied to Gi bound to neurotensin type 1 receptor (NTSR1) |
| GO:0016492 G protein-coupled neurotensin receptor activity | IDA PMID:21725197 Neurotensin receptor-1 inducible palmitoylation is required ... | ACCEPT | Summary: Direct assay in cells expressing human NTSR1: neurotensin stimulation drives receptor-Galphaq/11 coupling and ERK phosphorylation, both lost in the palmitoylation-deficient receptor. Reason: This is NTSR1's core molecular function. UniProt types it as the receptor for the tridecapeptide neurotensin; the purified human receptor binds the agonist and catalyses nucleotide exchange on Gq heterotrimers, and smFRET of human NTSR1-Gi ternary complexes shows agonist-dependent opening of the Galphai helical domain correlating with GTP turnover. Ligand-defined receptor activity of exactly this kind is what GO:0016492 states. Supporting Evidence: PMID:21725197 mutant failed to interact with GΞ± q/11 following 15 min stimulation with 1 Β΅M NTS PMID:21725197 only WT-NTSR-1 efficiently stimulated ERK phosphorylation PMID:21725197 dual-palmitoylation at Cys381 and Cys383 of endogenously-expressed NTSR-1 in |
| GO:0016492 G protein-coupled neurotensin receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro neurotensin-receptor signatures (IPR003984/IPR003985) map to neurotensin receptor activity. Reason: This is NTSR1's core molecular function. UniProt types it as the receptor for the tridecapeptide neurotensin; the purified human receptor binds the agonist and catalyses nucleotide exchange on Gq heterotrimers, and smFRET of human NTSR1-Gi ternary complexes shows agonist-dependent opening of the Galphai helical domain correlating with GTP turnover. Ligand-defined receptor activity of exactly this kind is what GO:0016492 states. The family-specific InterPro signatures are a sound basis for this ligand-specific term in a protein that is the defining member of the family. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt G protein-coupled receptor for the tridecapeptide neurotensin |
| GO:0016492 G protein-coupled neurotensin receptor activity | IMP PMID:8381365 Cloning and expression of a complementary DNA encoding a hig... | ACCEPT | Summary: Expression of the cloned human cDNA confers high-affinity neurotensin receptor pharmacology on otherwise non-responsive cells. Reason: This is NTSR1's core molecular function. UniProt types it as the receptor for the tridecapeptide neurotensin; the purified human receptor binds the agonist and catalyses nucleotide exchange on Gq heterotrimers, and smFRET of human NTSR1-Gi ternary complexes shows agonist-dependent opening of the Galphai helical domain correlating with GTP turnover. Ligand-defined receptor activity of exactly this kind is what GO:0016492 states. Heterologous expression reconstituting the pharmacology is the classic demonstration that this gene product enables the activity. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains PMID:17620610 binds the agonist neurotensin with a |
| GO:0030424 axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ultrastructural studies detect neurotensin receptor immunoreactivity in myelinated and unmyelinated axons, in addition to the dominant somatodendritic pool. Reason: Supported by the EM data, which report modest axonal labelling; axonal receptor is consistent with the presynaptic modulation of transmitter release attributed to NTSR1. A real but secondary location relative to the somatodendritic plasma membrane. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 modest localization in myelinated and unmyelinated axons and astrocytic |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin receptor protein is concentrated in dendrites of target neurons. Reason: Directly supported: immunogold and ligand-binding labels associate predominantly with somata and dendrites of presumptive dopaminergic neurons. Kept as a non-core neuronal compartment refinement of the core plasma-membrane location. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0032094 response to food | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 mediates the anorexigenic effect of central neurotensin; receptor-null mice eat more, weigh more and do not reduce feeding after i.c.v. neurotensin. Reason: Well supported by knockout data in mice and by NTSR1-biased pharmacology reducing palatable food intake, but this is an organismal feeding response rather than the receptor's core molecular role. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:12384239 I.c.v. injection of NT inhibited feeding in fasted wild-type PMID:12384239 clearly implicated in thermal and feeding regulation, weight control, and PMID:42146540 SBI-553 reduces palatable food consumption in both fed and food-deprived |
| GO:0032280 symmetric synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Localization of neurotensin receptor to symmetric (typically inhibitory) synaptic profiles in rodent brain. Reason: A fine-grained ultrastructural claim from the rodent literature that I cannot independently re-derive from the cached text, but it is consistent with NTSR1's documented modulation of GABAergic transmission and with receptor presence at both pre- and postsynaptic membranes; the cited EM study for human-side curation notes that most plasma-membrane receptor is extrasynaptic, so a synaptic pool is at best a minor location. Retained as non-core, deferring to the rodent curator. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 predominantly extrasynaptic |
| GO:0032960 regulation of inositol trisphosphate biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: NTSR1 activation stimulates phosphoinositide turnover: the receptor couples to Gq/11, activating PLC and raising inositol trisphosphate. Reason: This is a receptor-proximal, mechanistically direct consequence of NTSR1 activity. UniProt states that signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system; the purified receptor activates Gq heterotrimers, and the palmitoylation-dependent receptor-Galphaq/11 interaction is demonstrated in human cells. The receptor does the work of the first step (G protein activation) that drives IP3 production. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers PMID:21725197 mutant failed to interact with GΞ± q/11 following 15 min stimulation with 1 Β΅M NTS |
| GO:0033993 response to lipid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Broad 'response to lipid' row transferred from rat Ntsr1. Reason: NTSR1's ligand is a peptide, not a lipid. Lipids influence the system indirectly (dietary lipid triggers neurotensin release; the receptor's own activity depends on palmitoylation and on raft lipids), but 'response to lipid' as a process the receptor participates in is unsupported and uninformative. Flagged as over-annotation rather than removed because the receptor's behaviour is genuinely lipid-dependent at the membrane level. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Palmitoylated; this is required for normal localization at PMID:21725197 palmitoylation-deficient NTSR-1 localization within caveolinenriched SMDs is diminished upon NTS stimulation |
| GO:0040017 positive regulation of locomotion | IEA GO_REF:0000107 | MODIFY | Summary: Row asserting positive regulation of locomotion; in mice, central neurotensin acting at NTSR1 produces hypolocomotion, which is lost in NTSR1-null animals. Reason: The direction is not established as positive for NTSR1: knockout mice have normal spontaneous locomotion but fail to show NT-induced hypolocomotion, i.e. receptor activation decreases locomotor activity in that paradigm, while stimulant-interaction studies report activity increases in others. The sound claim is that NTSR1 modulates locomotion, so generalize to the sign-neutral parent GO:0040012 rather than keeping a direction the evidence contradicts. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Proposed replacements: regulation of locomotion Supporting Evidence: PMID:12384239 but did not respond to i.c.v. NT-induced PMID:12384239 clearly implicated in thermal and feeding regulation, weight control, and |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 homodimerizes; purified receptor self-associates with low-nanomolar apparent affinity and agonist binding becomes positively cooperative at dimer-favouring concentrations. Reason: The claim is specific and experimentally supported (orthology transfer from rat Ntsr1), and unlike bare protein binding, identical protein binding is informative about receptor self-association. It is kept, but as non-core: the same study shows monomers activate Gq while dimers exchange nucleotide less avidly, concluding that dimerization is not a prerequisite for G protein activation, so homodimerization modulates rather than constitutes the core function. Supporting Evidence: PMID:17620610 NTS1, a class A GPCR, dimerizes in detergent solution in a PMID:17620610 NTS1 dimerization per se is not a prerequisite for G protein activation PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0042802 identical protein binding | IPI PMID:17620610 Dimerization of the class A G protein-coupled neurotensin re... | KEEP AS NON CORE | Summary: NTSR1 homodimerizes; purified receptor self-associates with low-nanomolar apparent affinity and agonist binding becomes positively cooperative at dimer-favouring concentrations. Reason: The claim is specific and experimentally supported (purified human receptor shown to self-associate in a concentration-dependent manner), and unlike bare protein binding, identical protein binding is informative about receptor self-association. It is kept, but as non-core: the same study shows monomers activate Gq while dimers exchange nucleotide less avidly, concluding that dimerization is not a prerequisite for G protein activation, so homodimerization modulates rather than constitutes the core function. Supporting Evidence: PMID:17620610 NTS1, a class A GPCR, dimerizes in detergent solution in a PMID:17620610 NTS1 dimerization per se is not a prerequisite for G protein activation PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin receptor protein is abundant in neuronal perikarya of target neurons. Reason: Directly supported by the ultrastructural data associating label with somata and dendrites of presumptive dopaminergic neurons. A neuronal compartment refinement of the core plasma-membrane location. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | UNDECIDED | Summary: Row asserting that NTSR1 promotes apoptosis, transferred from rat Ntsr1; human-cell data show the opposite effect (neurotensin protects cells from serum-starvation apoptosis through NTSR1). Reason: The direction conflicts with the experimental human evidence that NTSR1 signaling is cytoprotective, and with UniProt's statement that signaling protects cells against apoptosis. The rodent source publication behind this Ensembl-Compara transfer is not accessible here, so I cannot see what was assayed (NT is pro-apoptotic in some settings), and I am unwilling to either accept a claim contradicted by the human data or remove an annotation whose experimental basis I have not read. Flagged UNDECIDED pending access to the rodent source. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:21725197 HEK293T cells transfected with WT-NTSR-1 and treated with 200 nM NTS showed less apoptosis relative to untreated cells PMID:21725197 reduced ability to protect HEK293T cells against apoptosis induced by serum file:human/NTSR1/NTSR1-uniprot.txt Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:21725197 Neurotensin receptor-1 inducible palmitoylation is required ... | KEEP AS NON CORE | Summary: Neurotensin stimulation of human NTSR1 protects cells from serum-starvation-induced apoptosis, and protection requires receptor palmitoylation at Cys381/Cys383. Reason: Directly supported by caspase-3/7 assays in cells expressing wild-type versus palmitoylation-deficient human receptor, and recorded by UniProt as part of the receptor's function. Cytoprotection is a downstream outcome of ERK/Akt-directed receptor signaling rather than the receptor's own activity, so it is kept as a non-core process. Supporting Evidence: PMID:21725197 HEK293T cells transfected with WT-NTSR-1 and treated with 200 nM NTS showed less apoptosis relative to untreated cells PMID:21725197 reduced ability to protect HEK293T cells against apoptosis induced by serum PMID:21725197 only WT-NTSR-1 efficiently stimulated ERK phosphorylation |
| GO:0043195 terminal bouton | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Presynaptic terminal-bouton localization of neurotensin receptor in rodent brain. Reason: Consistent with the axonal labelling seen ultrastructurally and with presynaptic modulation of transmitter release by neurotensin; a minor location compared with the somatodendritic pool. Retained as non-core, deferring to the rodent curator. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 modest localization in myelinated and unmyelinated axons and astrocytic |
| GO:0043197 dendritic spine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Dendritic-spine localization of neurotensin receptor. Reason: A fine-grained subdomain of the dendritic localization that the EM data support at the level of somata and dendrites; kept as non-core. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0043198 dendritic shaft | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Dendritic-shaft localization of neurotensin receptor. Reason: As for the dendritic-spine row: a subdomain refinement of the supported dendritic localization, and consistent with the homogeneous, predominantly extrasynaptic distribution along somatodendritic membranes. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons PMID:9763490 predominantly extrasynaptic |
| GO:0043204 perikaryon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perikaryal localization of neurotensin receptor, including an intracellular biosynthetic pool. Reason: Supported by the EM study, which finds abundant label in perikarya, partly over ER and Golgi membranes. A neuronal compartment rather than a core functional location. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons PMID:9763490 membranes of smooth endoplasmic reticulum and Golgi apparatus |
| GO:0043576 regulation of respiratory gaseous exchange | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Central neurotensin acting at NTSR1 alters respiratory output in rodents. Reason: A peripheral organismal role from the rodent literature, of the same family as NTSR1's documented autonomic effects (body temperature, blood pressure, feeding). I cannot re-derive the specific respiratory evidence from the cached material, so I defer to the rodent curator and keep it as clearly non-core rather than removing a claim I have not disproved. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:31243364 engages multiple subtypes of G protein |
| GO:0043679 axon terminus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Axon-terminus localization of neurotensin receptor. Reason: Consistent with the axonal labelling reported ultrastructurally and with presynaptic modulation of glutamate and GABA release; a secondary location. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 modest localization in myelinated and unmyelinated axons and astrocytic |
| GO:0044309 neuron spine | IEA GO_REF:0000107 | TOO GENERAL | Summary: Generic 'neuron spine' row alongside the more specific dendritic-spine row. Reason: GO:0043197 dendritic spine is a descendant of GO:0044309 neuron spine and is kept in this review, so the parent term adds nothing. The claim itself is not disputed. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:9763490 labels with somata and dendrites of presumptive dopaminergic neurons |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | MODIFY | Summary: Generic complex-binding row; the complexes NTSR1 demonstrably binds are heterotrimeric G proteins. Reason: The informative version of this claim is specific: human NTSR1 forms ternary complexes with intact Galphai-beta-gamma heterotrimers (cryo-EM structures with Gi1 and smFRET of purified NTSR1-Gi complexes) and activates Galphaq-beta1-gamma2 heterotrimers in reconstitution assays. Replace the uninformative parent with GO:0032795 heterotrimeric G-protein binding, which is what the structural and biochemical evidence establishes. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Proposed replacements: heterotrimeric G-protein binding Supporting Evidence: PMID:31243364 present structures of human NTSR1 in complex with the agonist JMV449 and the PMID:42870023 Full-length human NTSR1 was expressed and purified as previously described PMID:42870023 a pattern that also applied to Gi bound to neurotensin type 1 receptor (NTSR1) PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0045121 membrane raft | IDA PMID:21725197 Neurotensin receptor-1 inducible palmitoylation is required ... | ACCEPT | Summary: Fractionation of human-receptor-expressing cells shows NTSR1 in caveolin-rich membrane microdomains, dependent on Cys381/Cys383 palmitoylation. Reason: Raft/caveolin-enriched microdomain residence is directly demonstrated for the human receptor by detergent-free sucrose-gradient fractionation and is palmitoylation dependent: the C381,383S receptor loses raft localization and fails to couple to Galphaq/11. UniProt records membrane raft as a subcellular location and notes that palmitoylation is required for it. Because raft residence is required for efficient Gq coupling and mitogenic signaling, this is a functionally meaningful location, not an incidental one. Supporting Evidence: PMID:21725197 palmitoylation-deficient NTSR-1 localization within caveolinenriched SMDs is diminished upon NTS stimulation PMID:21725197 dual-palmitoylation at Cys381 and Cys383 of endogenously-expressed NTSR-1 in PMID:21725197 mutant failed to interact with GΞ± q/11 following 15 min stimulation with 1 Β΅M NTS |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (SL-0370 membrane raft). Reason: Raft/caveolin-enriched microdomain residence is directly demonstrated for the human receptor by detergent-free sucrose-gradient fractionation and is palmitoylation dependent: the C381,383S receptor loses raft localization and fails to couple to Galphaq/11. UniProt records membrane raft as a subcellular location and notes that palmitoylation is required for it. Because raft residence is required for efficient Gq coupling and mitogenic signaling, this is a functionally meaningful location, not an incidental one. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Palmitoylated; this is required for normal localization at PMID:21725197 palmitoylation-deficient NTSR-1 localization within caveolinenriched SMDs is diminished upon NTS stimulation |
| GO:0050965 detection of temperature stimulus involved in sensory perception of pain | IEA GO_REF:0000107 | REMOVE | Summary: Row implicating NTSR1 in thermal-stimulus detection for pain perception; targeted mouse genetics assigns this role to the paralog Ntsr2, not to Ntsr1. Reason: Two independent knockout studies contradict the claim. Ntsr1-null mice retain normal NT-induced analgesia and normal thermal nociception, with altered hot-plate jump latency seen only in Ntsr2-deficient animals, and the Ntsr1 knockout paper concludes the receptor does not mediate NT analgesia. Mechanistically the term also mis-types the receptor: detection of a temperature stimulus is performed by thermosensory transduction channels, not by a neuropeptide receptor. NTSR1's genuine thermal role is central thermoregulation, which is captured separately by GO:0001659. Supporting Evidence: PMID:14725975 results suggest that Ntsr2 has an important role in thermal nociception compared PMID:14725975 Ntsr1-deficient or wild-type control mice. Latencies of tail flick and hind paw PMID:12384239 the NT-1R does not play a role in NT-induced analgesia |
| GO:0051280 negative regulation of release of sequestered calcium ion into cytosol | IEA GO_REF:0000107 | UNDECIDED | Summary: Row asserting that NTSR1 decreases release of ER-sequestered calcium, opposite in sign to its canonical Gq/PLC/IP3-mediated mobilization of stored calcium. Reason: The canonical and well-documented action of NTSR1 is to raise cytosolic calcium through the phosphatidylinositol-calcium second messenger system, which is the positive-regulation row kept in this review. A negative-regulation role is conceivable in a receptor this promiscuous (Gi/Go coupling can oppose Gq outputs), but the rodent source publication behind this electronic transfer is not accessible here, so I cannot see what was measured. Marked UNDECIDED rather than accepting a contradictory sign or removing an annotation whose experimental basis I have not read. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system PMID:42870023 which couple promiscuously in vitro |
| GO:0051281 positive regulation of release of sequestered calcium ion into cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: NTSR1 activation mobilizes calcium from intracellular stores via Gq/11, PLC and IP3. Reason: This is the canonical NTSR1 second-messenger output and follows directly from receptor-catalysed Gq activation: UniProt describes signaling through a phosphatidylinositol-calcium second messenger system, the purified receptor activates Gq heterotrimers, and the receptor-Galphaq/11 interaction is shown in human cells. Reactome models the same step as the receptor acting as a GEF for Gq/11, whose IP3 product releases ER calcium. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers Reactome:R-HSA-379048 Liganded Gq/11-activating GPCRs act as GEFs for Gq/11 |
| GO:0060732 positive regulation of inositol phosphate biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: NTSR1 activation increases inositol phosphate production through Gq/11-dependent PLC activation. Reason: Mechanistically direct and well supported, as for the IP3-regulation row: the receptor performs the G protein activation step that drives PLC-dependent inositol phosphate generation, and its Galphaq/11 coupling is demonstrated for the human protein. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system PMID:21725197 mutant failed to interact with GΞ± q/11 following 15 min stimulation with 1 Β΅M NTS PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0070779 D-aspartate import across plasma membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Row placing NTSR1 in D-aspartate import across the plasma membrane, a transport process; NTSR1 is a receptor with no transport activity. Reason: Neurotensin signaling can change D-aspartate handling in neurons and astrocytes, but the entity that performs import across the plasma membrane is an amino-acid transporter, not a 7TM receptor. NTSR1 neither catalyses the translocation nor contributes structure or cofactor activity to it; at most it regulates the cells that do. Any real effect belongs in a regulatory term, so the involved_in claim is flagged as an over-annotation. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains |
| GO:0071545 inositol phosphate catabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Row placing NTSR1 in inositol phosphate catabolism. Reason: NTSR1 drives inositol phosphate *production* through Gq/PLC; the degradative arm is executed by inositol polyphosphate phosphatases. Stimulating phosphoinositide turnover increases flux through both arms, which is presumably what was measured, but the receptor performs no step of catabolism, so the involved_in claim overstates its role. The biosynthetic rows (GO:0032960, GO:0060732) capture what the receptor actually does. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0071625 vocalization behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rodent vocalization-behaviour role transferred from rat Ntsr1. Reason: A behavioural, circuit-level claim of the same kind as NTSR1's other documented rodent behavioural roles. I cannot re-derive the specific vocalization evidence from the cached material and will not overrule the rodent curator on it, but it is plainly peripheral to the receptor's core function. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:12384239 clearly implicated in thermal and feeding regulation, weight control, and |
| GO:0090238 positive regulation of arachidonate secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurotensin acting at NTSR1 stimulates arachidonic acid release, downstream of Gq/PLC/calcium and phospholipase A2 activation. Reason: A plausible and curator-supported downstream output that follows naturally from the receptor's calcium-mobilizing signaling, but the arachidonate release itself is performed by phospholipases. Kept as a non-core regulatory role. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers |
| GO:0097151 positive regulation of inhibitory postsynaptic potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 signaling strengthens inhibitory postsynaptic responses in limbic circuits. Reason: Supported in kind by NTSR1-selective pharmacology that changes GABAergic neurotransmission across extended amygdala subregions, and consistent with the receptor's modulation of GABA release. A circuit-level modulatory role, not a core receptor function. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:42146540 this LTP resulted from activation of NTSR1s rather than NTSR2s PMID:42146540 SBI-553 reduces palatable food consumption in both fed and food-deprived |
| GO:0098712 L-glutamate import across plasma membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Row placing NTSR1 in L-glutamate import across the plasma membrane, a transport process; NTSR1 is a receptor with no transport activity. Reason: Neurotensin signaling can change L-glutamate handling in neurons and astrocytes, but the entity that performs import across the plasma membrane is an amino-acid transporter, not a 7TM receptor. NTSR1 neither catalyses the translocation nor contributes structure or cofactor activity to it; at most it regulates the cells that do. Any real effect belongs in a regulatory term, so the involved_in claim is flagged as an over-annotation. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:8381365 amino acids with 7 transmembrane domains |
| GO:1990708 conditioned place preference | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 contributes to reward-related conditioned behaviours; NTSR1-directed biased ligands alter psychostimulant reward in rodents. Reason: Consistent with the human-receptor pharmacology showing that a beta-arrestin-biased NTSR1 modulator attenuates addictive behaviours while antagonizing the G protein arm, which demonstrates NTSR1 involvement in reward circuitry. Behavioural and peripheral to the core function. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. Supporting Evidence: PMID:32470395 selectively antagonizing G protein signaling |
| GO:2000822 regulation of behavioral fear response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NTSR1 signaling modulates fear-related behaviour in rodents. Reason: A behavioural role in limbic circuits where NTSR1 demonstrably tunes GABAergic transmission; the specific fear-conditioning evidence is in the rodent literature behind the transfer rather than in the cached material, so I defer to the curator and keep it as clearly non-core. This row is an Ensembl-Compara transfer (GO_REF:0000107) of an experimental annotation of rat Ntsr1 (P20789), the unambiguous 1:1 ortholog of human NTSR1; the rodent source publication is not in the local cache, so the claim is judged on the rodent literature as a whole. |
| GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway | IDA PMID:17620610 Dimerization of the class A G protein-coupled neurotensin re... | NEW | Summary: NTSR1 is a Gq/11-coupled receptor whose activation drives PLC-dependent phosphoinositide hydrolysis, IP3 generation and calcium mobilization; this pathway term is absent from GOA for NTSR1 although the receptor's downstream inositol-phosphate and calcium consequences are annotated. Reason: Participation: NTSR1 itself performs the first step of this pathway. Purified human NTS1 monomers catalyse nucleotide exchange on Galphaq-beta1-gamma2, and the palmitoylated receptor interacts with Galphaq/11 in human cells, with the coupling-deficient C381,383S mutant losing both the interaction and downstream ERK signaling; UniProt states that signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system, and Reactome models liganded NTSR1 as a GEF for Gq/11. The receptor is therefore the entity doing the work of activating the G protein that activates PLC, not merely something the pathway requires. Comparator check (QuickGO, October 2026): other peptide and amine Gq-coupled GPCRs in exactly the same role carry this term - AGTR1 has 13 annotations to GO:0007200, TACR1 has 5 and HTR2A has 4 - while NTSR1 and NTSR2 have none, so the absence is a gap rather than a GO convention about receptors. The term is neither an ancestor nor a descendant of any other term asserted here: it is a sibling-level refinement of GO:0007186 (marked TOO_GENERAL) that is more specific than the kept inositol-phosphate and calcium regulation rows and distinct from GO:0007218. Supporting Evidence: PMID:17620610 NTS1 monomers activate G alpha q beta(1)gamma(2), whereas receptor dimers PMID:21725197 mutant failed to interact with GΞ± q/11 following 15 min stimulation with 1 Β΅M NTS file:human/NTSR1/NTSR1-uniprot.txt Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system Reactome:R-HSA-379048 Liganded Gq/11-activating GPCRs act as GEFs for Gq/11 |
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Download this section (compressed HTML)Q: Which of NTSR1's many downstream physiological roles (thermoregulation, feeding, blood pressure, locomotion, reward) are mediated by the G protein arm and which by the beta-arrestin arm, and should GO capture arm-specific process annotations for a receptor whose two arms are pharmacologically separable?
Suggested experts: Lauren M. Slosky, Marc G. Caron, Lawrence S. Barak
Q: Given that NTSR1 couples promiscuously in vitro and is used as the benchmark promiscuous GPCR in G protein selectivity assays, which G protein classes should be reflected in its pathway annotations beyond Gq/11 - in particular, is the transferred cAMP-related annotation best expressed as GO:0007189?
Suggested experts: Brian K. Kobilka, Asuka Inoue, Hideaki E. Kato
Q: Is the symmetric-synapse and terminal-bouton localization of NTSR1 a functionally distinct presynaptic pool, or incidental labelling of a receptor whose plasma-membrane distribution is described as homogeneous and predominantly extrasynaptic?
Suggested experts: Alain Beaudet, Virginia M. Pickel
Q: Should palmitoylation-dependent membrane-raft residence of NTSR1 be modelled as a distinct active location (a prerequisite for Gq/11 coupling) rather than as an additional cellular component annotation?
Suggested experts: Mark Kester, Robert Levenson
Q: Do the rodent-transferred annotations for inositol phosphate catabolism and for D-aspartate / L-glutamate import across the plasma membrane reflect receptor-driven regulation that deserves a regulatory term, or should they be dropped as transport and degradative processes in which the receptor performs no step?
Suggested experts: GO cell signaling curators, RGD curators
Experiment: Express wild-type and C381,383S human NTSR1 in a raft-disrupted versus intact background and measure, side by side, raft partitioning, Galphaq/11 and Galphai recruitment (BRET), IP1/calcium responses, and beta-arrestin recruitment.
Hypothesis: Palmitoylation-dependent raft residence is required specifically for the Gq/11 arm of NTSR1 signaling, leaving arrestin recruitment largely intact, which would justify treating membrane raft as an active location for the Gq-coupled core function.
Experiment: Apply the smFRET Galphai helical-domain assay used for human NTSR1-Gi complexes across a panel of Galpha subtypes (Gq, G11, Gi1, GoA, Gs) with matched agonists and with SBI-553-family modulators, and correlate open-state occupancy with GTP turnover for each subtype.
Hypothesis: Agonist-induced helical-domain opening predicts efficacy for every G protein subtype NTSR1 engages, so promiscuity is set by how far the receptor opens each heterotrimer rather than by selective binding.
Experiment: In Ntsr1 and Ntsr2 single and double knockout mice, phenotype thermal nociception, core temperature, feeding and locomotion in the same cohorts, with NTSR1-selective and biased ligands as pharmacological controls.
Hypothesis: Thermal nociception maps onto Ntsr2 while thermoregulation and feeding map onto Ntsr1, confirming that GO:0050965 does not belong on NTSR1 and that its thermal role is homeostatic rather than sensory.
Experiment: In human colonic epithelial and colon cancer lines, compare neurotensin, a G protein-biased agonist and SBI-553 for NF-kB activation, miR-21/miR-155 induction, PTEN/SOCS1 suppression, Akt phosphorylation and anchorage-independent growth, with NTSR1 knockout rescue controls.
Hypothesis: The tumour-supporting gene-expression program downstream of NTSR1 requires the G protein arm, so beta-arrestin-biased modulators will not reproduce it - separating the receptor's oncogenic signaling from its arrestin-dependent outputs.
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