CTR1 (cephalotocin receptor 1) is a G protein-coupled receptor of the oxytocin/vasopressin receptor superfamily in Octopus vulgaris. It was cloned from octopus brain and shown to be specifically activated by cephalotocin (CT), an OT/VP superfamily neuropeptide, but not by octopressin (OP) or vertebrate OT/VP peptides. CTR1 signals via the inositol phosphate/Ca2+ pathway (Gq-coupled). It is the first invertebrate OT/VP-type receptor to be functionally characterized. Expression is detected in the central and peripheral nervous systems, pancreas, oviduct, and ovary, suggesting roles in neurotransmission, reproduction, and metabolism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: CTR1 is a confirmed GPCR. Functional expression in Xenopus oocytes demonstrated that it couples to G proteins to activate the inositol phosphate/Ca2+ signaling cascade upon cephalotocin binding (PMID:14596680). Sequence analysis places it in the rhodopsin-type (class I) GPCR family (PMID:15504101). Reason: This is a well-supported core annotation. CTR1 displays all hallmarks of GPCR activity: seven transmembrane domains, G protein coupling, and ligand-dependent activation of intracellular signaling. However, more specific child terms (neuropeptide receptor activity) are also applicable and are proposed as NEW annotations. Supporting Evidence: PMID:14596680 We cloned the cDNA of an orphan receptor from Octopus brain and found it to encode a polypeptide of 397 amino acids that displays sequences characteristic of G-protein coupled receptors. PMID:14596680 Xenopus oocytes that express the orphan receptor responded to the application of CT by an induction of membrane Cl(-) currents coupled to the inositol phosphate/Ca(2+) pathway. |
| GO:0005000 vasopressin receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: CTR1 belongs to the OT/VP receptor superfamily by sequence homology (InterPro:IPR001817), but its actual ligand is cephalotocin, not vasopressin. Vertebrate OT/VP peptides do not activate this receptor (PMID:14596680). The term "vasopressin receptor activity" (defined as "combining with vasopressin to initiate a change in cell activity") is therefore incorrect for this protein. Reason: While CTR1 is homologous to vasopressin receptors, the GO term GO:0005000 specifies binding vasopressin as ligand. CTR1 is specifically activated by cephalotocin and does not respond to vasopressin or other vertebrate OT/VP peptides. The appropriate term is GO:0008188 (neuropeptide receptor activity), which accurately captures the GPCR-mediated neuropeptide signaling function without implying incorrect ligand specificity. Proposed replacements: neuropeptide receptor activity Supporting Evidence: PMID:14596680 OP and the other members of the oxytocin/vasopressin superfamily did not activate this receptor. PMID:15504101 These invertebrate receptors are not activated by vertebrate OT/VP family peptides. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: CTR1 is a seven-transmembrane GPCR predicted to localize to the plasma membrane. UniProt annotates it as a cell membrane multi-pass membrane protein. Functional expression in Xenopus oocytes showed ligand-dependent signaling from the cell surface (PMID:14596680). Reason: Plasma membrane localization is the expected and functionally validated location for this GPCR. The protein has seven predicted transmembrane helices and functions by binding extracellular cephalotocin to activate intracellular signaling cascades. Supporting Evidence: PMID:14596680 Xenopus oocytes that express the orphan receptor responded to the application of CT by an induction of membrane Cl(-) currents coupled to the inositol phosphate/Ca(2+) pathway. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: CTR1 participates in GPCR signaling. Functional assays in Xenopus oocytes demonstrated that cephalotocin binding activates the inositol phosphate/Ca2+ signaling cascade, a hallmark of Gq-coupled GPCR signaling (PMID:14596680). Reason: This is a core annotation. The IEA annotation is well-supported by experimental evidence from the original cloning paper. A more specific child term (GO:0007218, neuropeptide signaling pathway) is also applicable and proposed as a NEW annotation. Supporting Evidence: PMID:14596680 Xenopus oocytes that express the orphan receptor responded to the application of CT by an induction of membrane Cl(-) currents coupled to the inositol phosphate/Ca(2+) pathway. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: CTR1 is a multi-pass transmembrane protein with seven predicted transmembrane helices (UniProt feature annotations). This annotation from InterPro2GO is correct but less specific than the plasma membrane annotation (GO:0005886) also present. Reason: Correct but generic. This IEA annotation from InterPro is subsumed by the more specific plasma membrane annotation. Acceptable to retain as a broad IEA annotation. |
| GO:0032870 cellular response to hormone stimulus | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: CTR1 mediates the cellular response to cephalotocin, a neuropeptide hormone of the OT/VP superfamily. This TreeGrafter annotation is broadly reasonable, as cephalotocin functions as a hormonal peptide in octopus physiology (PMID:14596680). Reason: While cephalotocin is a neuropeptide with hormone-like properties, this term is somewhat imprecise. The annotation from TreeGrafter reflects the broader OT/VP superfamily classification. It is not wrong but is not the most informative term for this receptor's function. The core function is better captured by neuropeptide receptor activity and neuropeptide signaling pathway annotations. Supporting Evidence: PMID:14596680 This receptor may mediate physiological functions of CT in Octopus such as neurotransmission, reproduction and metabolism. |
| GO:0042277 peptide binding | IEA GO_REF:0000118 | MODIFY | Summary: CTR1 binds cephalotocin, a neuropeptide ligand. However, "peptide binding" is overly generic and does not capture the signaling receptor function. The receptor does not merely bind peptide -- it transduces a signal via G protein coupling (PMID:14596680). Reason: The term "peptide binding" is too generic for a GPCR that specifically binds cephalotocin and activates intracellular signaling. More informative terms such as neuropeptide receptor activity (GO:0008188) better capture the actual molecular function. Peptide binding fails to distinguish a signaling receptor from a passive binding protein. Proposed replacements: neuropeptide receptor activity Supporting Evidence: PMID:14596680 HPLC fractionation of the Octopus brain extract combined with an oocyte assay yielded a single substance that was identical to CT. On the basis of these results, we conclude that the cloned receptor is the CT receptor (CTR). |
| GO:0016500 protein-hormone receptor activity | IDA PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | MODIFY | Summary: This IDA annotation from PMID:15504101 reflects that CTR1 functions as a receptor for the hormone-like neuropeptide cephalotocin. However, cephalotocin is a small neuropeptide (9 amino acids), not a protein hormone. The term "protein-hormone receptor activity" is defined as activity that combines with a protein hormone, which is a misnomer for a nonapeptide ligand. Reason: Cephalotocin is a nonapeptide (9 amino acids), not a protein hormone. The GO term GO:0016500 "protein-hormone receptor activity" implies binding a protein-sized ligand. GO:0008188 "neuropeptide receptor activity" is more accurate, as cephalotocin is a neuropeptide of the OT/VP superfamily. The neuropeptide receptor activity term is a child of G protein-coupled peptide receptor activity (GO:0008528), which correctly places it in the GPCR hierarchy. Proposed replacements: neuropeptide receptor activity Supporting Evidence: PMID:14596680 We cloned the cDNA of an orphan receptor from Octopus brain and found it to encode a polypeptide of 397 amino acids that displays sequences characteristic of G-protein coupled receptors. The orphan receptor showed high homology to receptors of the oxytocin/vasopressin superfamily. PMID:15504101 Previously, we cloned a GPCR (G-protein-coupled receptor) specific to CT [CTR1 (CT receptor 1)]. |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | ACCEPT | Summary: CTR1 signals through the GPCR signaling pathway, specifically the Gq/phospholipase C/ inositol phosphate/Ca2+ cascade. This TAS annotation based on PMID:15504101 is well supported by the original characterization in PMID:14596680. Reason: This is a core annotation with strong experimental support. CTR1 was functionally expressed in Xenopus oocytes and shown to activate inositol phosphate/Ca2+ signaling upon cephalotocin binding, confirming GPCR signaling pathway involvement. Supporting Evidence: PMID:14596680 Xenopus oocytes that express the orphan receptor responded to the application of CT by an induction of membrane Cl(-) currents coupled to the inositol phosphate/Ca(2+) pathway. PMID:15504101 OxyR, V1aR and V1bR, coupled to Gq/11, activate the inositol 1,4,5-trisphosphate–calcium signal transduction cascade |
| GO:0016020 membrane | IC PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | ACCEPT | Summary: This IC annotation infers membrane localization from the protein-hormone receptor activity annotation (with/from GO:0016500). As a seven-transmembrane GPCR, membrane localization is inherent to the protein's structure and function. Reason: Correct inference. A GPCR with seven transmembrane domains is by definition an integral membrane protein. The more specific plasma membrane annotation (GO:0005886) is also present. This IC annotation is redundant but not incorrect. Supporting Evidence: PMID:15504101 Previously, we cloned a GPCR (G-protein-coupled receptor) specific to CT [CTR1 (CT receptor 1)]. |
| GO:0008188 neuropeptide receptor activity | IDA PMID:14596680 Cloning of Octopus cephalotocin receptor, a member of the ox... | NEW | Summary: CTR1 was functionally characterized as a receptor specific to cephalotocin, a neuropeptide of the OT/VP superfamily, by expression in Xenopus oocytes with ligand-specific activation assays (PMID:14596680). This is the most accurate MF term for CTR1. Reason: Cephalotocin is a neuropeptide (nonapeptide of the OT/VP superfamily). CTR1 was experimentally shown to specifically bind cephalotocin and activate intracellular signaling via the inositol phosphate/Ca2+ cascade. GO:0008188 is a child of GO:0008528 (G protein-coupled peptide receptor activity) and GO:0004930 (GPCR activity), correctly placing CTR1 in the ontology hierarchy. This term replaces the incorrect vasopressin receptor activity and overly generic peptide binding annotations. Supporting Evidence: PMID:14596680 HPLC fractionation of the Octopus brain extract combined with an oocyte assay yielded a single substance that was identical to CT. On the basis of these results, we conclude that the cloned receptor is the CT receptor (CTR). PMID:14596680 OP and the other members of the oxytocin/vasopressin superfamily did not activate this receptor. |
| GO:0007218 neuropeptide signaling pathway | TAS PMID:14596680 Cloning of Octopus cephalotocin receptor, a member of the ox... | NEW | Summary: CTR1 mediates neuropeptide signaling by transducing cephalotocin binding into intracellular Ca2+ signaling. GO:0007218 is a child of GO:0007186 (GPCR signaling pathway) and more precisely describes the biological process. Reason: The neuropeptide signaling pathway term is more specific than the existing GPCR signaling pathway annotation and accurately reflects CTR1's role in transducing a neuropeptide (cephalotocin) signal. Expression in nervous system tissues (brain, buccal ganglion, gastric ganglion, optical lobe, peduncle lobe) supports a neuropeptide signaling role (PMID:14596680). Supporting Evidence: PMID:14596680 Expression of CTR mRNA in Octopus was detected in the central and the peripheral nervous systems, the pancreas, the oviduct and the ovary. This receptor may mediate physiological functions of CT in Octopus such as neurotransmission, reproduction and metabolism. |
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