CTR2 (cephalotocin receptor 2) is a G protein-coupled receptor of the oxytocin/vasopressin receptor superfamily in Octopus vulgaris. It is the second cephalotocin receptor identified in octopus (after CTR1). Functional expression in Xenopus oocytes demonstrated that CTR2 is specifically activated by cephalotocin (CT) via calcium-mediated signaling, but not by octopressin (OP) or vertebrate OT/VP peptides. Unlike CTR1, which is expressed primarily in the nervous system, CTR2 mRNA is mainly distributed in peripheral tissues with highest expression in branchia and vas deferens. Based on expression patterns and vertebrate analogy, CTR2 is proposed to mediate ammonia excretion (via branchia) and production/secretion of steroid hormones (via vas deferens and testis).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: CTR2 is a confirmed GPCR of the rhodopsin-type (class I) family. Functional expression in Xenopus oocytes demonstrated calcium-mediated inward chloride current upon cephalotocin stimulation, consistent with G protein coupling (PMID:15504101). Sequence analysis shows domains and motifs typical of GPCRs, and the gene has an intron between TM6 and TM7 consistent with OT/VP receptor gene structure. Reason: This is a well-supported core annotation. CTR2 has 7TM architecture, G protein coupling, and ligand-dependent activation of intracellular signaling. More specific child terms (neuropeptide receptor activity) are also applicable and proposed as NEW annotations. Consistent with ACCEPT decisions for CTR1 and OPR on the same term. Supporting Evidence: PMID:15504101 Both CTR2 and OPR include domains and motifs typical of GPCRs, and the intron-exon structures are in accord with those of OT/VP receptor genes. PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. |
| GO:0005000 vasopressin receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: CTR2 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 invertebrate OT/VP receptors including CTR2 (PMID:15504101). The term GO:0005000 is defined as combining with vasopressin to initiate a change in cell activity, which is incorrect for this protein. Reason: While CTR2 is homologous to vasopressin receptors, GO:0005000 specifies vasopressin as the ligand. CTR2 is specifically activated by cephalotocin and does not respond to vasopressin or other vertebrate OT/VP peptides. GO:0008188 (neuropeptide receptor activity) accurately captures the GPCR-mediated neuropeptide signaling function without implying incorrect ligand specificity. This is consistent with the MODIFY decisions made for CTR1 and OPR on the same term. Proposed replacements: neuropeptide receptor activity Supporting Evidence: PMID:15504101 These invertebrate receptors are not activated by vertebrate OT/VP family peptides. PMID:15504101 These results lead to the conclusion that CTR2 and OPR are receptors specific for CT and OP respectively. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: CTR2 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 demonstrated ligand-dependent signaling from the cell surface (PMID:15504101). 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. Consistent with ACCEPT for CTR1 and OPR. Supporting Evidence: PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: CTR2 participates in GPCR signaling. Functional assays in Xenopus oocytes demonstrated that cephalotocin binding activates calcium-mediated inward chloride current, a hallmark of Gq-coupled GPCR signaling via the inositol phosphate/Ca2+ cascade (PMID:15504101). Reason: This is a core annotation well supported by experimental evidence. A more specific child term (GO:0007218, neuropeptide signaling pathway) is also applicable and proposed as a NEW annotation. Consistent with ACCEPT for CTR1 and OPR. Supporting Evidence: PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: CTR2 is an integral membrane protein with 7 transmembrane domains, inferred from InterPro domain matches (IPR000276, IPR001817, IPR017452). This is a correct but generic CC annotation. Reason: Correct but redundant with the more specific GO:0005886 (plasma membrane) annotation. As an IEA from InterPro2GO mapping, it is acceptable to retain. Consistent with CTR1 and OPR reviews. |
| GO:0032870 cellular response to hormone stimulus | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: CTR2 mediates the cellular response to cephalotocin, a neuropeptide with hormone-like properties. Cephalotocin is distributed in the brain, particularly the subesophageal region (PMID:12972329), and acts as a neurohormone. CTR2 is mainly expressed in peripheral tissues, consistent with hormonal signaling (PMID:15504101). Reason: Cephalotocin has properties of both a neuropeptide and a neurohormone. The TreeGrafter annotation is broadly reasonable given CTR2 is a peripheral tissue receptor for a neuropeptide hormone. However, this term is not the most informative; the core function is better captured by neuropeptide receptor activity and neuropeptide signaling pathway annotations. Consistent with KEEP_AS_NON_CORE for CTR1. Supporting Evidence: PMID:15504101 CTR2 mRNA was mainly distributed in peripheral tissues, although CT did not induce contractile activities on the smooth muscles of several Octopus tissues. PMID:12972329 Cephalotocin may play important roles in metabolism, homeostasis, etc., as a neurohormone. |
| GO:0042277 peptide binding | IEA GO_REF:0000118 | MODIFY | Summary: CTR2 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:15504101). Reason: The term "peptide binding" is too generic for a GPCR that specifically binds cephalotocin and activates intracellular signaling. GO:0008188 (neuropeptide receptor activity) better captures the actual molecular function. Peptide binding fails to distinguish a signaling receptor from a passive binding protein. Consistent with MODIFY for CTR1 and OPR. Proposed replacements: neuropeptide receptor activity Supporting Evidence: PMID:15504101 These results lead to the conclusion that CTR2 and OPR are receptors specific for CT and OP respectively. |
| 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 CTR2 functions as a receptor for the hormone-like neuropeptide cephalotocin. However, cephalotocin is a small nonapeptide (9 amino acids), not a protein hormone. The term "protein-hormone receptor activity" is defined as combining with a protein hormone, which is a misnomer for a nonapeptide ligand. Reason: Cephalotocin is a nonapeptide (9 amino acids), not a protein hormone. GO:0016500 implies binding a protein-sized ligand. GO:0008188 (neuropeptide receptor activity) is more accurate, as cephalotocin is a neuropeptide of the OT/VP superfamily. This is consistent with the MODIFY decision for CTR1 on the same term. Proposed replacements: neuropeptide receptor activity Supporting Evidence: PMID:15504101 In the present study, we have identified an additional CTR, CTR2, and a novel OP receptor, OPR. PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | ACCEPT | Summary: CTR2 signals through the GPCR signaling pathway, specifically via calcium-mediated signaling consistent with the Gq/phospholipase C/inositol phosphate/Ca2+ cascade used by vertebrate OT/VP receptors (PMID:15504101). Reason: This is a core annotation with strong experimental support. CTR2 was functionally expressed in Xenopus oocytes and shown to activate calcium-mediated inward chloride current upon cephalotocin binding. Consistent with ACCEPT for CTR1 and OPR. Supporting Evidence: PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. 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. Consistent with CTR1 and OPR. Supporting Evidence: PMID:15504101 Both CTR2 and OPR include domains and motifs typical of GPCRs, and the intron-exon structures are in accord with those of OT/VP receptor genes. |
| GO:0046887 positive regulation of hormone secretion | TAS PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | KEEP AS NON CORE | Summary: This TAS annotation is based on the discussion in PMID:15504101 that CTR2 expression in vas deferens and testis, by analogy to mammalian VP receptor expression in Leydig cells, suggests that cephalotocin participates in production and/or secretion of steroid hormones via CTR2. This is a speculative extrapolation from expression data and vertebrate analogy, not direct experimental evidence of hormone secretion regulation. Reason: The paper proposes this function based on (1) CTR2 expression in vas deferens and testis, and (2) analogy to mammalian VP receptors regulating testosterone production in Leydig cells. However, no direct experimental evidence demonstrates that CTR2 activation positively regulates hormone secretion in octopus. The evidence is circumstantial and analogical. The annotation is plausible but speculative, so it is kept as non-core rather than accepted or removed. This annotation is unique to CTR2 (not present for CTR1 or OPR). Supporting Evidence: PMID:15504101 These findings, combined with the abundant expression of CTR2 in the vas deferens and testis, support a notion that CT participates in production and/or secretion of the steroid hormones via CTR2. |
| GO:0008188 neuropeptide receptor activity | IDA PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | NEW | Summary: CTR2 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:15504101). This is the most accurate MF term for CTR2. Reason: Cephalotocin is a neuropeptide (nonapeptide of the OT/VP superfamily). CTR2 was experimentally shown to specifically bind cephalotocin and activate calcium-mediated signaling. GO:0008188 is a child of GO:0008528 (G protein-coupled peptide receptor activity) and GO:0004930 (GPCR activity), correctly placing CTR2 in the ontology hierarchy. This term replaces the incorrect vasopressin receptor activity, overly generic peptide binding, and imprecise protein-hormone receptor activity annotations. Consistent with NEW annotations proposed for CTR1 and OPR. Supporting Evidence: PMID:15504101 These results lead to the conclusion that CTR2 and OPR are receptors specific for CT and OP respectively, and that these octopus receptors share a common ancestor with the vertebrate OT/VP receptors. PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. |
| GO:0007218 neuropeptide signaling pathway | TAS PMID:15504101 Novel evolutionary lineages of the invertebrate oxytocin/vas... | NEW | Summary: CTR2 mediates neuropeptide signaling by transducing cephalotocin binding into intracellular calcium signaling. GO:0007218 is a child of GO:0007186 (GPCR signaling pathway) and more precisely describes the biological process. Unlike CTR1, CTR2 is primarily expressed in peripheral tissues, suggesting hormonal/neuroendocrine signaling rather than neurotransmission. Reason: The neuropeptide signaling pathway term is more specific than the existing GPCR signaling pathway annotation and accurately reflects CTR2's role in transducing a neuropeptide (cephalotocin) signal. CTR2 expression in peripheral tissues including branchia, vas deferens, and testis supports a role in neuroendocrine peptide signaling. Consistent with NEW annotations for CTR1 and OPR. Supporting Evidence: PMID:15504101 CTR2 mRNA was mainly distributed in peripheral tissues, although CT did not induce contractile activities on the smooth muscles of several Octopus tissues. PMID:15504101 CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. |
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