CALCA

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: Calcitonin is a secreted peptide hormone released from thyroid parafollicular C cells into the bloodstream where it acts on osteoclasts to inhibit bone resorption. This localization is well-supported by phylogenetic inference and consistent with the UniProt annotation indicating calcitonin is secreted. The IBA annotation from phylogenetic analysis is appropriate for this conserved localization. Reason: Calcitonin is a secreted hormone that acts in the extracellular space. UniProt explicitly annotates SUBCELLULAR LOCATION as Secreted. Serum calcitonin levels have been measured clinically (PMID:18057382) confirming its presence in extracellular fluids. The IBA annotation correctly reflects this core localization. Supporting Evidence: PMID:18057382 Reference range of serum calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette smoking.
GO:0051480 regulation of cytosolic calcium ion concentration	IBA GO_REF:0000033	ACCEPT	Summary: Calcitonin is a calciotropic hormone whose primary physiological function involves regulating calcium homeostasis. It causes a rapid drop in blood calcium and phosphate levels by promoting incorporation into bones and inhibiting bone resorption. The IBA annotation appropriately captures this core biological process at the right level of specificity. Reason: Regulation of calcium ion concentration is a core function of calcitonin. UniProt describes calcitonin as a peptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in blood. Katacalcin is also described as a potent plasma calcium-lowering peptide (PMID:6132180). This is the defining biological process for calcitonin family peptides. Supporting Evidence: UniProt:P01258 Calcitonin is a peptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in blood by promoting the incorporation of those ions in the bones.
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: Calcitonin signals through the calcitonin receptor (CALCR), a class B GPCR that couples to Gs to activate adenylate cyclase and raise cAMP levels. This is a well-established and primary signaling mechanism for calcitonin action. The IBA annotation appropriately captures this core signaling pathway. Reason: Adenylate cyclase activation via Gs-coupled GPCR signaling is the primary signaling mechanism for calcitonin. Studies show calcitonin stimulates a cAMP response in osteoclasts and other cells (PMID:11014233, PMID:8078488). The deep research review confirms CGRP receptors primarily couple to Gs to raise cAMP/PKA. This is a core molecular function of the calcitonin family. Supporting Evidence: PMID:8078488 Calcitonin stimulates a cAMP response in both T47D and transfected baby hamster kidney cells. PMID:11014233 CT-sensitive adenylate cyclase responsiveness returned to the control levels by 96 h after removal of CT.
GO:0031716 calcitonin receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: Calcitonin receptor binding is the primary molecular function of calcitonin. The peptide hormone binds to the calcitonin receptor (CALCR) to mediate its biological effects. This is supported by extensive biochemical and structural evidence including cryo-EM structures of calcitonin bound to receptor complexes (PMID:35324283). The IBA annotation correctly identifies this core molecular function. Reason: Calcitonin receptor binding is the defining molecular function of calcitonin. Structural studies have determined the structure of calcitonin bound to CTR and AMYR complexes (PMID:35324283). Ligand binding studies show calcitonin has high affinity for the calcitonin receptor (PMID:8078488). Supporting Evidence: PMID:35324283 We determined the structure and dynamics of active AMYRs with amylin, AMY1R with salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT. PMID:8078488 Like the endogenous T47D receptor, the recombinant receptor has an equally high affinity for salmon and porcine calcitonin but a 3-4-fold lower affinity for human calcitonin.
GO:0005179 hormone activity	IEA GO_REF:0000120	ACCEPT	Summary: Calcitonin is a well-established peptide hormone secreted by thyroid parafollicular C cells. It acts as a calciotropic hormone regulating calcium and phosphate homeostasis. The IEA annotation based on InterPro domain mapping is correct and consistent with experimental evidence. Reason: Hormone activity is a core molecular function of calcitonin. UniProt annotation explicitly describes calcitonin as a peptide hormone. This IEA annotation is redundant with the IDA annotation for the same term but is acceptable.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: Calcitonin is a secreted peptide hormone that is released into the extracellular space. The IEA annotation based on domain/subcellular location mapping is correct. This term is broader than GO:0005615 (extracellular space) which is also annotated. Reason: Extracellular region is the correct localization for a secreted hormone. UniProt explicitly annotates SUBCELLULAR LOCATION as Secreted. Multiple annotations for this term exist (IEA, TAS, IBA) and all are consistent with the core function of calcitonin as a circulating hormone.
GO:0048018 receptor ligand activity	IEA GO_REF:0000117	ACCEPT	Summary: Calcitonin functions as a receptor ligand, binding to and activating the calcitonin receptor (CALCR). This general term is appropriate but less specific than the more informative annotation GO:0031716 (calcitonin receptor binding). Reason: Receptor ligand activity is correct for calcitonin. However, GO:0031716 (calcitonin receptor binding) is a more specific and informative term. This IEA annotation is acceptable as a broader annotation but the IBA for calcitonin receptor binding is preferred for curation purposes.
GO:0097646 calcitonin family receptor signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: Calcitonin is the ligand that initiates the calcitonin receptor signaling pathway by binding to CALCR and activating downstream Gs-coupled cAMP signaling. This IEA annotation correctly identifies involvement in this core signaling pathway. Reason: Calcitonin family receptor signaling pathway is a core biological process for calcitonin. The deep research confirms that calcitonin signals through CALCR to activate Gs and raise cAMP/PKA. This IEA annotation is consistent with the IDA annotation for the same term.
GO:0005515 protein binding	IPI PMID:17689535 The interaction between endogenous calcineurin and the plasm...	REMOVE	Summary: This annotation is based on a publication studying PMCA-calcineurin interactions in breast cancer cells. Reviewing the paper, this appears to study calcineurin (PPP3CA) and PMCA interactions, not CALCA (calcitonin). The gene symbol confusion likely arose from similarity between CALCA and calcineurin abbreviations. Reason: The publication PMID:17689535 studies the interaction between calcineurin and plasma membrane calcium-dependent ATPase (PMCA) isoforms. Calcineurin is PPP3CA/PPP3CB, not CALCA (calcitonin). This appears to be an erroneous annotation based on gene symbol confusion. The paper abstract states that PMCA2 and PMCA4 interact with calcineurin, not calcitonin. Supporting Evidence: PMID:17689535 we demonstrate that endogenous human PMCA2 and -4 both interact with the signal transduction phosphatase, calcineurin, whereas, no interaction was detected with PMCA1.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This annotation derives from a high-throughput yeast two-hybrid study mapping the human binary protein interactome. The interaction with ANKRD11 (X5D778) requires further validation. Protein binding is an uninformative term that does not specify the functional relationship. Reason: High-throughput interaction studies can generate false positives. The term protein binding is too general to be informative about calcitonin function. The primary function of calcitonin as a secreted hormone binding to CALCR is better captured by the calcitonin receptor binding annotation. This annotation should be retained but noted as non-core. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0042802 identical protein binding	IPI PMID:23395606 Identification of a novel 'aggregation-prone'/'amyloidogenic...	KEEP AS NON CORE	Summary: Human calcitonin is known to self-aggregate and form amyloid fibrils, which is the basis for this annotation. The study identified amyloidogenic determinant peptides in calcitonin that mediate self-assembly. This is a real biochemical property of calcitonin but represents pathological aggregation rather than a core physiological function. Reason: Calcitonin self-association and amyloid fibril formation is well-documented and relevant to medullary thyroid carcinoma pathology. However, this aggregation-prone behavior is not a core physiological function. The primary function is hormone activity via calcitonin receptor binding. This annotation should be retained as it documents a real biochemical property with clinical implications. Supporting Evidence: PMID:23395606 Calcitonin is a 32-residue polypeptide hormone, which takes part in calcium metabolism in bones. It may form amyloid fibrils. Amyloid fibrils are related with serious diseases known as amyloidoses. The amyloid form of calcitonin takes part in medullary thyroid carcinoma.
GO:0005615 extracellular space	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation for extracellular space is redundant with the IBA and IDA annotations for the same term. Calcitonin is a secreted hormone found in serum. Keeping multiple evidence codes for well-supported localizations is acceptable. Reason: Extracellular space localization is correct for calcitonin. Serum calcitonin levels have been measured clinically (PMID:18057382). This IEA annotation is redundant with IBA and IDA annotations for the same term but is acceptable.
GO:0030424 axon	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is transferred from rat ortholog based on Ensembl Compara. While the CALCA gene produces alpha-CGRP through alternative splicing which is expressed in sensory neurons, the calcitonin isoform (P01258) itself is primarily expressed in thyroid C cells. This localization may be more relevant to alpha-CGRP (P06881) than to calcitonin. Reason: Axonal localization is relevant for the alternatively spliced alpha-CGRP isoform expressed in sensory neurons, not the calcitonin peptide hormone. The deep research notes that alpha-CGRP is expressed in peripheral sensory neurons including trigeminal and dorsal root ganglia. However, this annotation applies to the P01258 entry which is the calcitonin precursor, not alpha-CGRP. Keep as non-core with the caveat that this may be more relevant to the CGRP splice variant.
GO:0042311 vasodilation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Vasodilation is a well-established function of alpha-CGRP, which is produced from the CALCA gene by alternative splicing. CGRP is described in the deep research as a potent vasodilatory neuropeptide. However, calcitonin itself (the peptide from this UniProt entry) is not primarily a vasodilator - that function is specific to CGRP. Reason: Vasodilation is a core function of alpha-CGRP (P06881) produced by alternative splicing of the CALCA gene, not of calcitonin (P01258) itself. The deep research describes CGRP as acting at vascular smooth muscle as a potent vasodilator. This annotation likely derives from ortholog transfer that does not distinguish between splice variants. Keep as non-core to acknowledge the gene-level function while noting it is not the primary function of the calcitonin peptide.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal cell body localization is more relevant to the alpha-CGRP splice variant that is expressed in sensory neurons (trigeminal ganglia, dorsal root ganglia), not to calcitonin which is secreted from thyroid C cells. This annotation derives from ortholog transfer. Reason: The deep research describes alpha-CGRP as expressed in peripheral sensory neurons including trigeminal and DRG neurons. Calcitonin (the product of this UniProt entry) is secreted from thyroid C cells, not neurons. Keep as non-core to acknowledge that the CALCA gene product (as CGRP) is found in neurons while noting this is not the calcitonin peptide function.
GO:0045776 negative regulation of blood pressure	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Blood pressure lowering is a consequence of vasodilation, which is a function of alpha-CGRP rather than calcitonin itself. CGRP causes vasodilation and thus reduces blood pressure. This annotation derives from ortholog transfer and reflects the gene-level function. Reason: Negative regulation of blood pressure is secondary to the vasodilatory activity of alpha-CGRP produced from the CALCA gene. Calcitonin (P01258) itself is not known for blood pressure regulation. Keep as non-core to acknowledge this is a gene-level function via the CGRP splice variant.
GO:0045986 negative regulation of smooth muscle contraction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Relaxation of smooth muscle (vasodilation) is a function of alpha-CGRP acting on vascular smooth muscle cells. This is not a primary function of calcitonin. The annotation derives from ortholog transfer. Reason: Smooth muscle relaxation leading to vasodilation is a function of alpha-CGRP, not calcitonin. The deep research describes CGRP as acting at vascular smooth muscle. Keep as non-core to reflect gene-level function via the CGRP splice variant.
GO:0071356 cellular response to tumor necrosis factor	IEA GO_REF:0000107	UNDECIDED	Summary: This annotation suggests calcitonin or CGRP is involved in TNF response. While procalcitonin (the calcitonin prohormone) is induced during sepsis and inflammation, this annotation appears to conflate response to TNF with calcitonin expression regulation. Reason: The relationship between CALCA gene products and TNF response is unclear. Procalcitonin is a sepsis biomarker induced during systemic inflammation, but this does not mean calcitonin mediates cellular responses to TNF. This annotation from ortholog transfer requires further evidence to evaluate. The original reference for the rat ortholog annotation is not available for review.
GO:0098686 hippocampal mossy fiber to CA3 synapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This highly specific synaptic localization annotation likely derives from rat ortholog transfer. CGRP is expressed in sensory neurons and has been detected in various CNS regions. However, this specific localization to hippocampal mossy fiber synapses is overly specific for the UniProt calcitonin entry. Reason: This annotation is too specific without clear supporting evidence for human calcitonin. While CGRP has CNS expression, hippocampal mossy fiber synapse localization is a very specific claim. The calcitonin peptide (P01258) is primarily a thyroid-derived hormone acting on bone. This annotation should be marked as over-annotation.
GO:0098992 neuronal dense core vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuropeptides like CGRP are stored in and released from dense core vesicles in neurons. This annotation is relevant to alpha-CGRP expressed in sensory neurons but not to calcitonin secreted from thyroid C cells. Thyroid C cells are neuroendocrine cells that may also use dense core vesicles, but this annotation specifies neuronal vesicles. Reason: Dense core vesicle localization is relevant to neuropeptide secretion. CGRP is released from sensory neurons via dense core vesicles. While calcitonin from C cells may also be secreted via secretory granules, the annotation specifically refers to neuronal dense core vesicles. Keep as non-core to acknowledge CGRP function.
GO:1990090 cellular response to nerve growth factor stimulus	IEA GO_REF:0000107	UNDECIDED	Summary: This annotation suggests CALCA expression is regulated by NGF or that CALCA products mediate responses to NGF. CGRP expression in sensory neurons may be regulated by NGF signaling. This annotation derives from ortholog transfer. Reason: The relationship between CALCA/CGRP and NGF response in sensory neurons is plausible but the original evidence is not available for review. NGF is known to regulate neuropeptide expression in sensory neurons. Without access to the original rat evidence, cannot confirm if this applies to the calcitonin peptide (P01258) or is specific to CGRP.
GO:0005576 extracellular region	TAS Reactome:R-HSA-379044	ACCEPT	Summary: This Reactome annotation for extracellular region derives from the pathway reaction showing calcitonin acting as an extracellular ligand for Gs-activating GPCRs. Calcitonin is a secreted hormone that acts in the extracellular space. Reason: Extracellular region is the correct localization for calcitonin. This TAS annotation from Reactome pathway curation is consistent with the IBA and IDA annotations for extracellular space. Calcitonin acts as an extracellular ligand for CALCR.
GO:0005576 extracellular region	TAS Reactome:R-HSA-419843	ACCEPT	Summary: This Reactome annotation derives from the reaction CALCA(83-119) binds CALCR, showing calcitonin as an extracellular ligand binding to the calcitonin receptor. Correctly places calcitonin in the extracellular compartment. Reason: Extracellular region is correct for calcitonin which binds CALCR as an extracellular ligand. The Reactome reference specifically models calcitonin-receptor binding.
GO:0005576 extracellular region	TAS Reactome:R-HSA-744886	ACCEPT	Summary: This Reactome annotation from the Ligand:GPCR:Gs complex dissociation pathway places calcitonin in the extracellular region as expected for a secreted hormone ligand. Reason: Extracellular region is the correct localization for calcitonin. Redundant with other extracellular annotations but consistent with pathway modeling.
GO:0005576 extracellular region	TAS Reactome:R-HSA-744887	ACCEPT	Summary: This Reactome annotation from the GPCR-Gs binding pathway correctly places calcitonin as an extracellular ligand. Reason: Extracellular region is correct. Redundant with other annotations for this localization but acceptable for pathway context.
GO:0005576 extracellular region	TAS Reactome:R-HSA-9702354	ACCEPT	Summary: This Reactome annotation from the reaction CALCA(83-119) binds CALCA antibodies places calcitonin in the extracellular region where it can be bound by therapeutic antibodies. Reason: Extracellular region is correct. Calcitonin is a circulating hormone that can be targeted by antibodies in the extracellular space.
GO:0005576 extracellular region	TAS Reactome:R-HSA-976734	ACCEPT	Summary: This annotation from the amyloid fibril pathway places calcitonin in the extracellular region where amyloid deposits can form. Calcitonin amyloid is found in medullary thyroid carcinoma. Reason: Extracellular region is correct. Calcitonin amyloid deposits form extracellularly in pathological conditions.
GO:0005576 extracellular region	TAS Reactome:R-HSA-977136	ACCEPT	Summary: This annotation from the amyloid fibril formation pathway correctly places calcitonin in the extracellular region where amyloid precursor proteins can aggregate. Reason: Extracellular region is correct for calcitonin. This Reactome pathway models amyloid formation from extracellular calcitonin.
GO:0005179 hormone activity	IDA PMID:35324283 A structural basis for amylin receptor phenotype.	ACCEPT	Summary: Hormone activity is a core molecular function of calcitonin. The structural study PMID:35324283 demonstrates calcitonin binding to and activating its receptor complexes (CTR and AMYR2), which is the mechanistic basis for its hormone activity. Reason: Calcitonin is a well-established peptide hormone. The cryo-EM structures show calcitonin binding to CTR and AMYR complexes in active conformations, directly demonstrating its ability to act as a hormone ligand. Supporting Evidence: PMID:35324283 We determined the structure and dynamics of active AMYRs with amylin, AMY1R with salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
GO:0097646 calcitonin family receptor signaling pathway	IDA PMID:35324283 A structural basis for amylin receptor phenotype.	ACCEPT	Summary: Calcitonin is the prototypical ligand of the calcitonin receptor signaling pathway. The structural study demonstrates calcitonin bound to CTR in active G protein-coupled conformations, directly supporting its role in this signaling pathway. Reason: Calcitonin family receptor signaling pathway is a core biological process for calcitonin. The cryo-EM structures in PMID:35324283 show calcitonin bound to CTR-G protein complexes, providing direct structural evidence for calcitonin activating this pathway. Supporting Evidence: PMID:35324283 We determined the structure and dynamics of active AMYRs with amylin, AMY1R with salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
GO:0150060 amylin receptor 2 signaling pathway	IDA PMID:35324283 A structural basis for amylin receptor phenotype.	ACCEPT	Summary: UniProt explicitly states that calcitonin function is mediated by the CALCR-RAMP2 (AMYR2) receptor complex, and the structural study shows calcitonin bound to AMY2R. Calcitonin can signal through amylin receptor 2 in addition to CTR. Reason: The structural study PMID:35324283 directly demonstrates calcitonin bound to AMY2R (CTR+RAMP2) in active conformations. UniProt annotation also notes that calcitonin function is mediated by CALCR-RAMP2 complex. This is a legitimate signaling pathway for calcitonin. Supporting Evidence: PMID:35324283 Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY1R, AMY2R, and AMY3R.
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	IDA PMID:11014233 Calcitonin receptor regulation and responsiveness to calcito...	ACCEPT	Summary: The study demonstrates that calcitonin treatment activates adenylate cyclase in human osteoclast-like cells. Calcitonin-sensitive adenylate cyclase responsiveness was measured to track receptor function and desensitization. Reason: Adenylate cyclase activation is a core signaling mechanism for calcitonin. The study directly measures CT-sensitive adenylate cyclase responsiveness in human osteoclasts, providing experimental evidence for this pathway. Supporting Evidence: PMID:11014233 The reduced specific binding, CTR messenger RNA levels, and CT-sensitive adenylate cyclase responsiveness returned to the control levels by 96 h after removal of CT.
GO:0002548 monocyte chemotaxis	IDA PMID:15248232 Expression and function of RANK in human monocyte chemotaxis...	REMOVE	Summary: This publication studies RANKL-induced monocyte chemotaxis, not calcitonin. The study demonstrates that RANKL stimulates monocyte migration via RANK. Calcitonin is not directly studied in this paper; this appears to be an erroneous annotation. Reason: PMID:15248232 studies RANKL (TNFSF11) and its receptor RANK (TNFRSF11A), not calcitonin (CALCA). The abstract clearly states that RANKL stimulates monocyte chemotaxis via RANK. There is no evidence in this paper for calcitonin involvement in monocyte chemotaxis. This annotation should be removed as it appears to be incorrectly attributed to CALCA. Supporting Evidence: PMID:15248232 RANKL significantly stimulated monocyte chemotaxis via activation of phosphatidylinositol 3-kinase, phosphodiesterase, and Src kinase.
GO:0005615 extracellular space	IDA PMID:18057382 Reference range of serum calcitonin levels in humans: influe...	ACCEPT	Summary: This study measures serum calcitonin levels using immunoassays, directly demonstrating that calcitonin is present in the extracellular space (serum/blood). This is direct experimental evidence for extracellular localization. Reason: The study measured serum calcitonin concentrations in healthy subjects using multiple immunoassays, providing direct experimental evidence that calcitonin is secreted into and present in the extracellular space (blood/serum). Supporting Evidence: PMID:18057382 The objective of this study was to re-evaluate the adult C(T) reference values determined by five different immunoassays and by introducing criteria for selecting control subjects.
GO:0007204 positive regulation of cytosolic calcium ion concentration	IDA PMID:17983652 Calcitonin promotes outgrowth of trophoblast cells on endome...	ACCEPT	Summary: The study shows that calcitonin treatment causes rapid increases in cytosolic calcium levels in endometrial epithelial cells. This calcium mobilization is part of the signaling mechanism by which calcitonin promotes trophoblast outgrowth. Reason: The study directly demonstrates that calcitonin exposure causes rapid increase in cytosolic calcium in endometrial epithelial cells. This is direct experimental evidence for calcitonin-induced calcium mobilization. Note this is distinct from the IBA annotation for GO:0051480 (regulation of cytosolic calcium ion concentration) which is about systemic calcium homeostasis. Supporting Evidence: PMID:17983652 Cytosolic calcium (Ca(2+)) levels in EEC increased rapidly upon exposure to calcitonin, and blockade of Ca(2+) release by BAPTA-AM effectively prevented the promoting effect of calcitonin on trophoblast expansion on EEC.
GO:0007566 embryo implantation	IDA PMID:17983652 Calcitonin promotes outgrowth of trophoblast cells on endome...	KEEP AS NON CORE	Summary: The study demonstrates that calcitonin promotes trophoblast cell outgrowth on endometrial epithelial cells, suggesting a role in facilitating embryo implantation. However, this is an in vitro cell culture study and embryo implantation is a complex organismal process. Reason: While the study provides evidence that calcitonin facilitates trophoblast-endometrial interaction in vitro, embryo implantation is not a core function of calcitonin. The primary function of calcitonin is calcium homeostasis and bone resorption inhibition. The role in implantation is a secondary/pleiotropic effect. Keep as non-core. Supporting Evidence: PMID:17983652 calcitonin promotes trophoblastic displacement of EEC through calcium mobilization and PKC activation, thereby facilitating embryo implantation.
GO:0032147 activation of protein kinase activity	IDA PMID:17983652 Calcitonin promotes outgrowth of trophoblast cells on endome...	ACCEPT	Summary: The study shows that calcitonin activates protein kinase C (PKC) in endometrial epithelial cells as part of its signaling mechanism. PKC activation is downstream of calcium mobilization induced by calcitonin. Reason: PKC activation is part of the calcitonin signaling mechanism demonstrated in this study. This is consistent with the broader understanding of calcitonin receptor signaling through both adenylate cyclase and PKC pathways. Supporting Evidence: PMID:17983652 The Ca(2+)-dependent protein kinase C (PKC) was also activated in EEC after calcitonin treatment, and the PKC inhibitors staurosporine and calphostin C could completely abolish calcitonin-induced augmentation of trophoblast expansion on EEC.
GO:0045779 negative regulation of bone resorption	IDA PMID:17241109 Regulation and enzymatic basis of bone resorption by human o...	ACCEPT	Summary: Inhibition of bone resorption is a core physiological function of calcitonin. The study directly demonstrates that calcitonin dose-dependently inhibits bone resorption by human osteoclasts in vitro. This is the classical pharmacological action of calcitonin. Reason: Negative regulation of bone resorption is a core function of calcitonin. The study uses a functional assay measuring CTX-I release (collagen degradation product) and shows calcitonin dose-dependently inhibits resorption. This is consistent with the deep research noting that calcitonin rapidly inhibits osteoclast activity. Supporting Evidence: PMID:17241109 CT (calcitonin) dose-dependently inhibited bone resorption, whereas PTH (parathyroid hormone), IL (interleukin)-1, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-8, VEGF (vascular endothelial growth factor), MCP-1 (monocyte chemoattractant protein-1), MIP-1gamma (macrophage inflammatory protein-1gamma), IFN (interferon)-gamma and dibutyryl cGMP had no significant effect.
GO:0031716 calcitonin receptor binding	IPI PMID:8078488 Cloning and characterization of an abundant subtype of the h...	ACCEPT	Summary: This study cloned and characterized the human calcitonin receptor and demonstrated calcitonin binding to the recombinant receptor with high affinity. Binding studies directly demonstrate the physical interaction between calcitonin and its receptor. Reason: Calcitonin receptor binding is a core molecular function. The study directly measures calcitonin binding to cloned human CTR and demonstrates high affinity binding. This is experimental evidence for the primary ligand-receptor interaction. Supporting Evidence: PMID:8078488 Like the endogenous T47D receptor, the recombinant receptor has an equally high affinity for salmon and porcine calcitonin but a 3-4-fold lower affinity for human calcitonin.
GO:0031716 calcitonin receptor binding	IPI PMID:8940110 The deletion of 14 amino acids in the seventh transmembrane ...	ACCEPT	Summary: This study characterized calcitonin binding to different CTR isoforms including a novel splice variant. Binding studies with salmon and human calcitonin demonstrate the physical interaction with receptor isoforms. Reason: The study directly measures calcitonin binding to CTR isoforms, demonstrating the ligand-receptor interaction. This is experimental evidence supporting calcitonin receptor binding as a core molecular function. Supporting Evidence: PMID:8940110 Deletion of the residues in the seventh transmembrane domain in CTRDeltae13 reduced the binding affinity for salmon and human calcitonin by more than 10-fold and approximately 2-fold, respectively, resulting in a receptor that failed to discriminate between the two forms of calcitonin.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:11014233 Calcitonin receptor regulation and responsiveness to calcito...	KEEP AS NON CORE	Summary: The study shows that calcitonin treatment reduces CTR mRNA expression levels in osteoclasts, indicating negative regulation of transcription. This is part of the receptor down-regulation mechanism. Reason: The study demonstrates that calcitonin treatment reduces calcitonin receptor (CTR) mRNA levels, which is a form of negative transcriptional regulation. However, this is a secondary effect related to receptor desensitization rather than a primary function of calcitonin. Keep as non-core. Supporting Evidence: PMID:11014233 Treatment with sCT reduced CTR messenger RNA expression, suggesting that CTR down-regulation is, at least partly, attributable to an inhibition of de novo CTR synthesis.

Core Functions

Calcitonin receptor binding is the primary molecular function of calcitonin. The peptide hormone binds with high affinity to the calcitonin receptor (CALCR), a class B GPCR, to initiate downstream signaling. Structural studies have determined cryo-EM structures of calcitonin bound to CTR and amylin receptor complexes (PMID:35324283).

Molecular Function:

calcitonin receptor binding

Directly Involved In:

calcitonin family receptor signaling pathway negative regulation of bone resorption regulation of cytosolic calcium ion concentration

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:35324283
We determined the structure and dynamics of active AMYRs with amylin, AMY1R with salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
PMID:8078488
Like the endogenous T47D receptor, the recombinant receptor has an equally high affinity for salmon and porcine calcitonin but a 3-4-fold lower affinity for human calcitonin.

Calcitonin is a peptide hormone secreted by thyroid parafollicular C cells. It acts as a classical hormone, traveling through the bloodstream to target tissues (primarily bone) where it binds its receptor to exert calciotropic effects. Calcitonin causes a rapid drop in blood calcium by inhibiting osteoclast-mediated bone resorption.

Molecular Function:

hormone activity

Directly Involved In:

adenylate cyclase-activating G protein-coupled receptor signaling pathway

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:18057382
The objective of this study was to re-evaluate the adult C(T) reference values determined by five different immunoassays and by introducing criteria for selecting control subjects.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11014233

Calcitonin receptor regulation and responsiveness to calcitonin in human osteoclast-like cells prepared in vitro using receptor activator of nuclear factor-kappaB ligand and macrophage colony-stimulating factor.

PMID:15248232

Expression and function of RANK in human monocyte chemotaxis.

PMID:17241109

Regulation and enzymatic basis of bone resorption by human osteoclasts.

PMID:17689535

The interaction between endogenous calcineurin and the plasma membrane calcium-dependent ATPase is isoform specific in breast cancer cells.

PMID:17983652

Calcitonin promotes outgrowth of trophoblast cells on endometrial epithelial cells: involvement of calcium mobilization and protein kinase C activation.

PMID:18057382

Reference range of serum calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette smoking.

PMID:23395606

Identification of a novel 'aggregation-prone'/'amyloidogenic determinant' peptide in the sequence of the highly amyloidogenic human calcitonin.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:35324283

A structural basis for amylin receptor phenotype.

PMID:8078488

Cloning and characterization of an abundant subtype of the human calcitonin receptor.

PMID:8940110

The deletion of 14 amino acids in the seventh transmembrane domain of a naturally occurring calcitonin receptor isoform alters ligand binding and selectively abolishes coupling to phospholipase C.

Reactome:R-HSA-379044

Liganded Gs-activating GPCR acts as a GEF for Gs

Reactome:R-HSA-419843

CALCA(83-119) binds CALCR

Reactome:R-HSA-744886

The Ligand:GPCR:Gs complex dissociates

Reactome:R-HSA-744887

Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs

Reactome:R-HSA-9702354

CALCA(83-119) binds CALCA antibodies

Reactome:R-HSA-976734

Amyloid fibrils have additional components

Reactome:R-HSA-977136

Amyloid precursor proteins form ordered fibrils

Deep Research

Falcon

(CALCA-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 23 citations 2026-02-08T20:31:38.863939

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan and verification
- Identity confirmed: CALCA (HGNC:1437) encodes a secreted prepropeptide that yields calcitonin (CT) in thyroidal C cells and, via alternative splicing in neurons, α-calcitonin gene-related peptide (αCGRP). Procalcitonin (PCT) is an intermediate in CT biosynthesis and is markedly induced in systemic bacterial infection (sepsis) (jiang2024rolesofcalcitonin pages 17-20). The organism is human, and functions align with the calcitonin/CGRP peptide family and their class B GPCR receptors modulated by RAMPs (garelja2025calcitoninreceptorsin pages 1-3, garelja2025calcitoninreceptorsin pages 4-6).

Key concepts and definitions (current understanding)
- Gene products and alternative splicing: CALCA produces two principal bioactive peptides: CT (thyroidal) and αCGRP (neuronal) via alternative transcription/splicing; PCT is the CT prohormone and a systemic inflammation biomarker with low basal levels that rise strongly during sepsis (publication notes <0.1 ng/mL baseline) (Jiang 2024; Canadian musculoskeletal review excerpts) (jiang2024rolesofcalcitonin pages 17-20). In bone and marrow contexts, CT inhibits osteoclast motility and resorption in vitro, while genetic studies suggest αCGRP promotes bone formation; CALCA or CTR deficiency paradoxically increases bone formation via altered osteoclast–osteoblast crosstalk, underscoring distinct physiological roles of CT versus αCGRP (jiang2024rolesofcalcitonin pages 17-20, jiang2024rolesofcalcitonin pages 20-24).
- Receptors and complexes: The canonical CGRP receptor is a heterodimer of CALCRL (also called CLR) with RAMP1; CTR (CALCR) forms functional amylin receptors with RAMPs (e.g., AMY1 = CTR+RAMP1). Some CGRP pathway therapeutics (erenumab, gepants) can also engage AMY1 pharmacology, illustrating cross-reactivity within the calcitonin family receptor network (bhakta2021migrainetherapeuticsdifferentially pages 1-2, garelja2025calcitoninreceptorsin pages 1-3, garelja2025calcitoninreceptorsin pages 4-6).
- Primary signaling: CGRP receptors primarily couple to Gs to raise cAMP/PKA; β-arrestin recruitment, receptor phosphorylation and internalization occur after activation. Additional signaling via Ca2+/MAPK and, context-dependently, other cascades have been reported for calcitonin-family receptors (bhakta2021migrainetherapeuticsdifferentially pages 1-2, garelja2025calcitoninreceptorsin pages 7-9).
- Localization and secretion: CT is secreted from thyroid C cells into circulation; αCGRP is abundantly expressed in sensory neurons (e.g., trigeminovascular and dorsal root ganglia) and acts as a potent vasodilatory neuropeptide in pain/nociception circuits (jiang2024rolesofcalcitonin pages 17-20, bhakta2021migrainetherapeuticsdifferentially pages 1-2).

Recent developments and latest research (priority 2023–2024)
- Clinical practice guidelines advancing CGRP-targeting as first-line for migraine prevention:
- American Headache Society (AHS) 2024 position statement (Headache, March 2024): Concludes that CGRP-targeting therapies are a first-line option for prevention of migraine, removing prior requirements to fail multiple legacy preventives (https://doi.org/10.1111/head.14692; Mar 2024) (medrea2024updatedcanadianheadache pages 1-2) (medrea2024updatedcanadianheadache pages 1-2).
- Updated Canadian Headache Society Guideline 2024 (Canadian Journal of Neurological Sciences, November 2024): Systematic review (61 studies) and recommendations include anti-CGRP agents as options for episodic and chronic migraine prevention in Canada; the update also reappraises legacy preventives (e.g., topiramate downgraded to weak recommendation for episodic migraine; weak recommendation against gabapentin; weak recommendations for memantine/levetiracetam/enalapril/melatonin) (https://doi.org/10.1017/cjn.2024.285; Nov 2024) (medrea2024updatedcanadianheadache pages 1-2, medrea2024updatedcanadianheadache pages 9-10).
- Real-world uptake and utilization (United States claims data): In a 2024 Frontiers in Neurology cohort (IQVIA PharMetrics Plus), 22,584 chronic migraine (CM) and 216,807 non-chronic migraine (non-CM) patients were analyzed. Over follow-up, anti-CGRP monoclonal antibodies were dispensed to 28.9% of CM patients and to 6.9%, 4.1%, and 2.9% of non-CM patients in the highest, middle, and lowest tertiles of acute medication use, respectively (published Aug 6, 2024; https://doi.org/10.3389/fneur.2024.1433423) (khodavirdi2024treatmentpatternsof pages 1-2).
- Receptor pharmacology nuances of approved therapies: Comparative mechanistic work shows that the CGRP receptor antibody erenumab and small-molecule antagonists inhibit CGRP signaling at CLR/RAMP1 and also antagonize amylin signaling at AMY1 (CTR/RAMP1), whereas a CGRP-ligand antibody (fremanezumab) selectively blocks CGRP signaling without affecting AMY1, indicating clinically relevant target selectivity differences (Cephalalgia, Feb 2021; DOI: https://doi.org/10.1177/0333102420983282; mechanistic principles informing 2023–2024 practice) (bhakta2021migrainetherapeuticsdifferentially pages 1-2).
- Structure–mechanism insights: Recent computational/biophysical analyses integrate cryo-EM and ectodomain binding kinetics to elaborate the “two-domain” binding mechanism for CGRP at CLR/RAMP1 and peptide- and G protein–state–dependent affinities, relevant to designing long-acting peptides/gepants (bioRxiv, Jun 2025; https://doi.org/10.1101/2025.06.13.659569; supports the mechanistic framework used in 2023–2024 drug development) (kilinc2025determinantsofimproved pages 18-20).

Current applications and real-world implementations
- Migraine prevention and acute treatment: Multiple anti-CGRP monoclonal antibodies (fremanezumab, galcanezumab, eptinezumab) and a receptor-targeting mAb (erenumab), as well as small-molecule receptor antagonists (ubrogepant, rimegepant), are in routine clinical use. Guideline-level endorsements (AHS 2024; Canadian 2024) position these as first-line (AHS) or recommended options (Canada) for prevention, reflecting robust RCT and real-world evidence (medrea2024updatedcanadianheadache pages 1-2, medrea2024updatedcanadianheadache pages 9-10, bhakta2021migrainetherapeuticsdifferentially pages 1-2, khodavirdi2024treatmentpatternsof pages 1-2).
- Biomarker utility: Procalcitonin, a CALCA gene product intermediate, is a widely used clinical biomarker for bacterial infection/sepsis due to its marked systemic induction during infection; its basal concentrations are low in health, and pathophysiologic roles include modulation of inflammatory mediators (Jiang 2024 review excerpts) (jiang2024rolesofcalcitonin pages 17-20).
- Skeletal/bone biology: CT has long-standing anti-resorptive pharmacology on osteoclasts; however, genetic evidence indicates αCGRP favors bone formation, while loss of CT signaling via CTR can increase bone formation by altering osteoclast-derived S1P and osteoblast stimulation—nuances that inform modern interpretations of calcitonin-family roles in bone turnover (Jiang 2024 review excerpts; additional family-level background in IUPHAR-linked summaries) (jiang2024rolesofcalcitonin pages 17-20, jiang2024rolesofcalcitonin pages 20-24, garelja2025calcitoninreceptorsin pages 1-3).

Expert opinions and analyses from authoritative sources
- AHS Position Statement Update (2024): Concludes CGRP-targeting therapies are appropriate first-line options for preventive treatment, based on safety/efficacy evidence and clinical experience, moving away from step-therapy with legacy agents (Headache; https://doi.org/10.1111/head.14692; Mar 2024) (medrea2024updatedcanadianheadache pages 1-2).
- Canadian Headache Society (2024): Recommends anti-CGRP agents among preventive options and updates the evidence grading across preventives. The guideline emphasizes both episodic and chronic migraine contexts and integrates systematic review/meta-analysis to inform clinical decision-making (https://doi.org/10.1017/cjn.2024.285; Nov 2024) (medrea2024updatedcanadianheadache pages 1-2, medrea2024updatedcanadianheadache pages 9-10).

Relevant statistics and recent data points
- 22,584 CM and 216,807 non-CM patients analyzed in US claims; anti-CGRP mAb dispensing during follow-up: 28.9% (CM), and 6.9%/4.1%/2.9% across descending tertiles of acute-medicine use in non-CM (Frontiers in Neurology; Aug 6, 2024; https://doi.org/10.3389/fneur.2024.1433423) (khodavirdi2024treatmentpatternsof pages 1-2).
- Guideline evidence synthesis: 61 studies included; 16 therapies focused; explicit inclusion and approvals of anti-CGRP agents in Canada between 2018 and 2024; multiple recommendation adjustments (Canadian Journal of Neurological Sciences; Nov 2024; https://doi.org/10.1017/cjn.2024.285) (medrea2024updatedcanadianheadache pages 1-2).

Mechanisms, pathways, and structural biology (precise functional roles)
- αCGRP signaling: Endogenous ligand for CLR/RAMP1 CGRP receptor. Activates Gs→cAMP/PKA and engages β-arrestin–dependent receptor internalization; distribution in the trigeminovascular system substantiates its central role in migraine pathophysiology (bhakta2021migrainetherapeuticsdifferentially pages 1-2).
- Target selectivity and receptor crosstalk: Anti-CGRP receptor agents (e.g., erenumab) and some gepants also antagonize AMY1 (CTR/RAMP1), whereas anti-ligand antibodies (e.g., fremanezumab) are selective for CGRP—important for interpreting clinical response and adverse event profiles (bhakta2021migrainetherapeuticsdifferentially pages 1-2).
- CT signaling: Acts via CTR (CALCR), a class B GPCR, to suppress osteoclast activity; CTR plus RAMPs define amylin receptors (AMY1–3), contributing to complex pharmacology among calcitonin-family peptides (garelja2025calcitoninreceptorsin pages 1-3, garelja2025calcitoninreceptorsin pages 4-6).
- Two-domain binding model and RAMP1 role: Structural and kinetic studies support a two-domain peptide–GPCR interaction for CGRP at CLR/RAMP1, with peptide C-terminal anchoring in the receptor ectodomain and N-terminal engagement of the transmembrane core; RAMP1 is essential for ligand selectivity and receptor pharmacology (bioRxiv 2025 mechanistic synthesis; links to cryo-EM literature) (kilinc2025determinantsofimproved pages 18-20). Broader receptor/RAMP biology and accessory proteins (e.g., CGRP-RCP) shape trafficking and coupling efficiency across the calcitonin/adrenomedullin/amylin receptor families (garelja2025calcitoninreceptorsin pages 4-6, garelja2025calcitoninreceptorsin pages 7-9).

Cellular compartments and tissue context
- CT: Secreted endocrine hormone from thyroid C cells; targets osteoclasts in bone (inhibitory) and contributes to systemic calcium homeostasis. Genetic and cell-biology studies reveal CT can reduce osteoclast lamellipodial dynamics and motility (jiang2024rolesofcalcitonin pages 17-20).
- αCGRP: Secreted neuropeptide from sensory neurons; acts in the peripheral and central nervous systems and vasculature to mediate vasodilation and nociception; robustly present in trigeminovascular afferents (bhakta2021migrainetherapeuticsdifferentially pages 1-2).
- PCT: Circulating prohormone that serves as a sepsis biomarker; can influence inflammatory mediator profiles and has reported effects on osteoclastogenesis (jiang2024rolesofcalcitonin pages 17-20).

Limitations and open questions
- Sex hormone regulation of the CGRP system is an active research area (e.g., trigeminal ganglion expression dynamics), but our current evidence set does not include primary 2023–2024 human-focused mechanistic studies to cite; dedicated hormone–RAMP–CGRP regulatory interactions require further targeted sourcing (garelja2025calcitoninreceptorsin pages 7-9, garelja2025calcitoninreceptorsin pages 1-3).

Embedded summary table
| CALCA-derived peptide (human) | Receptor / complex (human nomenclature) | Primary signaling | Principal sites of action / localization | Core physiological role(s) | Key recent sources (year) |
|---|---|---|---|---|---|
| Calcitonin (CT) | Calcitonin receptor (CALCR / CTR); can form amylin receptors with RAMPs (CTR+RAMPs) | Gs → ↑cAMP/PKA (also reported MAPK/PKC modulation) | Secreted from thyroid parafollicular (C) cells; acts on bone (osteoclasts), kidney, and bone marrow niches | Rapid inhibition of osteoclast activity and bone resorption; systemic calciotropic regulator (pharmacologic anti-resorptive agent) | Jiang 2024 (jiang2024rolesofcalcitonin pages 20-24); Garelja 2025 (garelja2025calcitoninreceptorsin pages 1-3); Bhakta 2021 (bhakta2021migrainetherapeuticsdifferentially pages 1-2) |
| Alpha‑CGRP (αCGRP) | CGRP receptor = CALCRL + RAMP1 (canonical); cross-reactivity with AMY1 (CTR+RAMP1) reported | Gs → ↑cAMP/PKA; β‑arrestin recruitment/internalization; possible Gq/MAPK pathways | Expressed in peripheral sensory neurons (trigeminal, DRG), vasculature, CNS compartments; acts at vascular smooth muscle, sensory terminals, bone cells | Potent vasodilator and neuropeptide in nociception (central to migraine pathophysiology); promotes osteogenesis/vascularization in bone contexts | Bhakta 2021 (bhakta2021migrainetherapeuticsdifferentially pages 1-2); Kilinc/Babin 2025 (kilinc2025determinantsofimproved pages 18-20); Garelja 2025 (garelja2025calcitoninreceptorsin pages 4-6) |
| Procalcitonin (PCT) — prohormone / biomarker | Circulating prohormone processed to CT/CGRP isoforms; specific receptor interactions incompletely defined (functional effects reported on CGRP/related systems) | Modulates inflammatory signaling (reports of ↑IL‑6, TNFα in vitro); bone-related signaling effects observed | Basal low-level production (thyroid); markedly increased systemic levels in bacterial sepsis and systemic inflammation; local effects in bone marrow/osteoclast lineage | Clinical biomarker for bacterial infection/sepsis; experimentally reported to inhibit early osteoclast formation and modulate inflammation (pathophysiologic and diagnostic roles) | Jiang 2024 (jiang2024rolesofcalcitonin pages 17-20); Jiang 2024 (jiang2024rolesofcalcitonin pages 20-24) |

Table: Compact summary table of the three primary human CALCA-derived peptides (calcitonin, α‑CGRP, procalcitonin), their receptors/complexes, main signaling modes, principal sites of action, physiological roles, and key recent sources (context citations) useful for functional annotation and translational context.

References (with URLs/dates where available)
- American Headache Society Position Statement Update: Calcitonin gene–related peptide–targeting therapies as first-line for prevention of migraine. Headache. Mar 2024. https://doi.org/10.1111/head.14692 (medrea2024updatedcanadianheadache pages 1-2).
- Updated Canadian Headache Society Migraine Prevention Guideline with Systematic Review and Meta-analysis. Canadian Journal of Neurological Sciences. Nov 2024. https://doi.org/10.1017/cjn.2024.285 (medrea2024updatedcanadianheadache pages 1-2, medrea2024updatedcanadianheadache pages 9-10).
- Khodavirdi AC et al. Treatment patterns of patients with migraine eligible for anti-CGRP pathway monoclonal antibodies. Frontiers in Neurology. Aug 6, 2024. https://doi.org/10.3389/fneur.2024.1433423 (khodavirdi2024treatmentpatternsof pages 1-2).
- Bhakta M et al. Migraine therapeutics differentially modulate the CGRP pathway. Cephalalgia. Feb 2021. https://doi.org/10.1177/0333102420983282 (mechanistic pharmacology informing 2023–2024 practice) (bhakta2021migrainetherapeuticsdifferentially pages 1-2).
- Garelja ML, Hay D, Poyner DR. Calcitonin receptors in GtoPdb v. 2025.3. 2025. Contextual review of calcitonin-family receptors and RAMP modulation (garelja2025calcitoninreceptorsin pages 1-3, garelja2025calcitoninreceptorsin pages 7-9, garelja2025calcitoninreceptorsin pages 4-6).
- Jiang S. Roles of Calcitonin Family of Peptides in Degenerative Musculoskeletal Diseases. 2024. Synthesis of bone-relevant actions of CT, αCGRP, PCT (jiang2024rolesofcalcitonin pages 17-20, jiang2024rolesofcalcitonin pages 20-24).
- Kilinc C et al. Determinants of Improved CGRP Peptide Binding Kinetics Revealed by Enhanced Molecular Simulations. bioRxiv. Jun 2025. https://doi.org/10.1101/2025.06.13.659569 (two-domain binding/kinetic insights) (kilinc2025determinantsofimproved pages 18-20).

References

(jiang2024rolesofcalcitonin pages 17-20): S Jiang. Roles of calcitonin family of peptides in degenerative musculoskeletal diseases. Unknown journal, 2024.
(garelja2025calcitoninreceptorsin pages 1-3): ML Garelja, D Hay, and DR Poyner. Calcitonin receptors in gtopdb v. 2025.3. Unknown journal, 2025.
(garelja2025calcitoninreceptorsin pages 4-6): ML Garelja, D Hay, and DR Poyner. Calcitonin receptors in gtopdb v. 2025.3. Unknown journal, 2025.
(jiang2024rolesofcalcitonin pages 20-24): S Jiang. Roles of calcitonin family of peptides in degenerative musculoskeletal diseases. Unknown journal, 2024.
(bhakta2021migrainetherapeuticsdifferentially pages 1-2): Minoti Bhakta, Trang Vuong, Tetsuya Taura, David S Wilson, Jennifer R Stratton, and Kimberly D Mackenzie. Migraine therapeutics differentially modulate the cgrp pathway. Cephalalgia, 41:499-514, Feb 2021. URL: https://doi.org/10.1177/0333102420983282, doi:10.1177/0333102420983282. This article has 105 citations and is from a domain leading peer-reviewed journal.
(garelja2025calcitoninreceptorsin pages 7-9): ML Garelja, D Hay, and DR Poyner. Calcitonin receptors in gtopdb v. 2025.3. Unknown journal, 2025.
(medrea2024updatedcanadianheadache pages 1-2): Ioana Medrea, Paul Cooper, Marissa Langman, Claire H. Sandoe, Farnaz Amoozegar, Wasif M. Hussain, Ana C. Bradi, Jessica Dawe, Meagan Guay, Francois Perreault, Stuart Reid, Candice Todd, Becky Skidmore, and Suzanne N. Christie. Updated canadian headache society migraine prevention guideline with systematic review and meta-analysis. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 52:450-472, Nov 2024. URL: https://doi.org/10.1017/cjn.2024.285, doi:10.1017/cjn.2024.285. This article has 20 citations.
(medrea2024updatedcanadianheadache pages 9-10): Ioana Medrea, Paul Cooper, Marissa Langman, Claire H. Sandoe, Farnaz Amoozegar, Wasif M. Hussain, Ana C. Bradi, Jessica Dawe, Meagan Guay, Francois Perreault, Stuart Reid, Candice Todd, Becky Skidmore, and Suzanne N. Christie. Updated canadian headache society migraine prevention guideline with systematic review and meta-analysis. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 52:450-472, Nov 2024. URL: https://doi.org/10.1017/cjn.2024.285, doi:10.1017/cjn.2024.285. This article has 20 citations.
(khodavirdi2024treatmentpatternsof pages 1-2): Ani C. Khodavirdi, Jasjit K. Multani, Sam S. Oh, Fiston Vuvu, Mark E. Bensink, Karen M. Stockl, Kevin Hawkins, Chia-Chun Chiang, A. L. Green, Stewart J. Tepper, W. Masocha, Marta Waliszewska-Prosół, and A. Özge. Treatment patterns of patients with migraine eligible for anti-cgrp pathway monoclonal antibodies. Frontiers in Neurology, Aug 2024. URL: https://doi.org/10.3389/fneur.2024.1433423, doi:10.3389/fneur.2024.1433423. This article has 0 citations and is from a peer-reviewed journal.
(kilinc2025determinantsofimproved pages 18-20): Ceren Kilinc, Katie M. Babin, Augen A. Pioszak, and Alex Dickson. Determinants of improved cgrp peptide binding kinetics revealed by enhanced molecular simulations. bioRxiv, Jun 2025. URL: https://doi.org/10.1101/2025.06.13.659569, doi:10.1101/2025.06.13.659569. This article has 0 citations and is from a poor quality or predatory journal.

Citations

jiang2024rolesofcalcitonin pages 17-20
medrea2024updatedcanadianheadache pages 1-2
khodavirdi2024treatmentpatternsof pages 1-2
bhakta2021migrainetherapeuticsdifferentially pages 1-2
kilinc2025determinantsofimproved pages 18-20
jiang2024rolesofcalcitonin pages 20-24
garelja2025calcitoninreceptorsin pages 1-3
garelja2025calcitoninreceptorsin pages 4-6
garelja2025calcitoninreceptorsin pages 7-9
medrea2024updatedcanadianheadache pages 9-10
https://doi.org/10.1111/head.14692;
https://doi.org/10.1017/cjn.2024.285;
https://doi.org/10.3389/fneur.2024.1433423
https://doi.org/10.1177/0333102420983282;
https://doi.org/10.1101/2025.06.13.659569;
https://doi.org/10.1017/cjn.2024.285
https://doi.org/10.1111/head.14692
https://doi.org/10.1177/0333102420983282
https://doi.org/10.1101/2025.06.13.659569
https://doi.org/10.1177/0333102420983282,
https://doi.org/10.1017/cjn.2024.285,
https://doi.org/10.3389/fneur.2024.1433423,
https://doi.org/10.1101/2025.06.13.659569,

📄 View Raw YAML

id: P01258
gene_symbol: CALCA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >
  CALCA encodes the calcitonin precursor protein, a secreted peptide hormone precursor that is
  proteolytically processed to yield calcitonin (CT) and katacalcin. Calcitonin is a 32-amino acid
  peptide hormone secreted primarily by thyroid parafollicular (C) cells that functions as a
  calciotropic hormone regulating calcium and phosphate homeostasis. Its primary molecular function
  is binding to the calcitonin receptor (CALCR), a class B GPCR, to activate Gs-coupled adenylate
  cyclase signaling. The principal physiological effect is rapid inhibition of osteoclast-mediated
  bone resorption. Through alternative splicing, the CALCA gene also produces alpha-CGRP
  (calcitonin gene-related peptide, UniProtKB:P06881), a potent vasodilatory neuropeptide expressed
  in sensory neurons. Katacalcin, the C-terminal flanking peptide of calcitonin, also possesses
  plasma calcium-lowering activity.
existing_annotations:
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >
        Calcitonin is a secreted peptide hormone released from thyroid parafollicular C cells into
        the bloodstream where it acts on osteoclasts to inhibit bone resorption. This localization
        is well-supported by phylogenetic inference and consistent with the UniProt annotation
        indicating calcitonin is secreted. The IBA annotation from phylogenetic analysis is
        appropriate for this conserved localization.
      action: ACCEPT
      reason: >
        Calcitonin is a secreted hormone that acts in the extracellular space. UniProt explicitly
        annotates SUBCELLULAR LOCATION as Secreted. Serum calcitonin levels have been measured
        clinically (PMID:18057382) confirming its presence in extracellular fluids. The IBA
        annotation correctly reflects this core localization.
      supported_by:
        - reference_id: PMID:18057382
          supporting_text: >
            Reference range of serum calcitonin levels in humans: influence of calcitonin
            assays, sex, age, and cigarette smoking.
  - term:
      id: GO:0051480
      label: regulation of cytosolic calcium ion concentration
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >
        Calcitonin is a calciotropic hormone whose primary physiological function involves
        regulating calcium homeostasis. It causes a rapid drop in blood calcium and phosphate
        levels by promoting incorporation into bones and inhibiting bone resorption. The IBA
        annotation appropriately captures this core biological process at the right level of
        specificity.
      action: ACCEPT
      reason: >
        Regulation of calcium ion concentration is a core function of calcitonin. UniProt describes
        calcitonin as a peptide hormone that causes a rapid but short-lived drop in the level of
        calcium and phosphate in blood. Katacalcin is also described as a potent plasma
        calcium-lowering peptide (PMID:6132180). This is the defining biological process for
        calcitonin family peptides.
      supported_by:
        - reference_id: UniProt:P01258
          supporting_text: >
            Calcitonin is a peptide hormone that causes a rapid but short-lived drop in the level
            of calcium and phosphate in blood by promoting the incorporation of those ions in the
            bones.
  - term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >
        Calcitonin signals through the calcitonin receptor (CALCR), a class B GPCR that couples
        to Gs to activate adenylate cyclase and raise cAMP levels. This is a well-established
        and primary signaling mechanism for calcitonin action. The IBA annotation appropriately
        captures this core signaling pathway.
      action: ACCEPT
      reason: >
        Adenylate cyclase activation via Gs-coupled GPCR signaling is the primary signaling
        mechanism for calcitonin. Studies show calcitonin stimulates a cAMP response in
        osteoclasts and other cells (PMID:11014233, PMID:8078488). The deep research review
        confirms CGRP receptors primarily couple to Gs to raise cAMP/PKA. This is a core
        molecular function of the calcitonin family.
      supported_by:
        - reference_id: PMID:8078488
          supporting_text: >
            Calcitonin stimulates a cAMP response in both T47D and transfected baby hamster
            kidney cells.
        - reference_id: PMID:11014233
          supporting_text: >
            CT-sensitive adenylate cyclase responsiveness returned to the control levels by 96 h
            after removal of CT.
  - term:
      id: GO:0031716
      label: calcitonin receptor binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >
        Calcitonin receptor binding is the primary molecular function of calcitonin. The peptide
        hormone binds to the calcitonin receptor (CALCR) to mediate its biological effects. This
        is supported by extensive biochemical and structural evidence including cryo-EM structures
        of calcitonin bound to receptor complexes (PMID:35324283). The IBA annotation correctly
        identifies this core molecular function.
      action: ACCEPT
      reason: >
        Calcitonin receptor binding is the defining molecular function of calcitonin. Structural
        studies have determined the structure of calcitonin bound to CTR and AMYR complexes
        (PMID:35324283). Ligand binding studies show calcitonin has high affinity for the
        calcitonin receptor (PMID:8078488).
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:35324283
          supporting_text: >
            We determined the structure and dynamics of active AMYRs with amylin, AMY1R with
            salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
        - reference_id: PMID:8078488
          supporting_text: >
            Like the endogenous T47D receptor, the recombinant receptor has an equally high
            affinity for salmon and porcine calcitonin but a 3-4-fold lower affinity for human
            calcitonin.
  - term:
      id: GO:0005179
      label: hormone activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >
        Calcitonin is a well-established peptide hormone secreted by thyroid parafollicular
        C cells. It acts as a calciotropic hormone regulating calcium and phosphate homeostasis.
        The IEA annotation based on InterPro domain mapping is correct and consistent with
        experimental evidence.
      action: ACCEPT
      reason: >
        Hormone activity is a core molecular function of calcitonin. UniProt annotation explicitly
        describes calcitonin as a peptide hormone. This IEA annotation is redundant with the IDA
        annotation for the same term but is acceptable.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >
        Calcitonin is a secreted peptide hormone that is released into the extracellular space.
        The IEA annotation based on domain/subcellular location mapping is correct. This term is
        broader than GO:0005615 (extracellular space) which is also annotated.
      action: ACCEPT
      reason: >
        Extracellular region is the correct localization for a secreted hormone. UniProt explicitly
        annotates SUBCELLULAR LOCATION as Secreted. Multiple annotations for this term exist
        (IEA, TAS, IBA) and all are consistent with the core function of calcitonin as a
        circulating hormone.
  - term:
      id: GO:0048018
      label: receptor ligand activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >
        Calcitonin functions as a receptor ligand, binding to and activating the calcitonin
        receptor (CALCR). This general term is appropriate but less specific than the more
        informative annotation GO:0031716 (calcitonin receptor binding).
      action: ACCEPT
      reason: >
        Receptor ligand activity is correct for calcitonin. However, GO:0031716 (calcitonin
        receptor binding) is a more specific and informative term. This IEA annotation is
        acceptable as a broader annotation but the IBA for calcitonin receptor binding is
        preferred for curation purposes.
  - term:
      id: GO:0097646
      label: calcitonin family receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >
        Calcitonin is the ligand that initiates the calcitonin receptor signaling pathway by
        binding to CALCR and activating downstream Gs-coupled cAMP signaling. This IEA
        annotation correctly identifies involvement in this core signaling pathway.
      action: ACCEPT
      reason: >
        Calcitonin family receptor signaling pathway is a core biological process for calcitonin.
        The deep research confirms that calcitonin signals through CALCR to activate Gs and raise
        cAMP/PKA. This IEA annotation is consistent with the IDA annotation for the same term.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17689535
    review:
      summary: >
        This annotation is based on a publication studying PMCA-calcineurin interactions in
        breast cancer cells. Reviewing the paper, this appears to study calcineurin (PPP3CA)
        and PMCA interactions, not CALCA (calcitonin). The gene symbol confusion likely arose
        from similarity between CALCA and calcineurin abbreviations.
      action: REMOVE
      reason: >
        The publication PMID:17689535 studies the interaction between calcineurin and plasma
        membrane calcium-dependent ATPase (PMCA) isoforms. Calcineurin is PPP3CA/PPP3CB, not
        CALCA (calcitonin). This appears to be an erroneous annotation based on gene symbol
        confusion. The paper abstract states that PMCA2 and PMCA4 interact with calcineurin,
        not calcitonin.
      supported_by:
        - reference_id: PMID:17689535
          supporting_text: >
            we demonstrate that endogenous human PMCA2 and -4 both interact with the signal
            transduction phosphatase, calcineurin, whereas, no interaction was detected with
            PMCA1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >
        This annotation derives from a high-throughput yeast two-hybrid study mapping the human
        binary protein interactome. The interaction with ANKRD11 (X5D778) requires further
        validation. Protein binding is an uninformative term that does not specify the functional
        relationship.
      action: MARK_AS_OVER_ANNOTATED
      reason: >
        High-throughput interaction studies can generate false positives. The term protein
        binding is too general to be informative about calcitonin function. The primary function
        of calcitonin as a secreted hormone binding to CALCR is better captured by the calcitonin
        receptor binding annotation. This annotation should be retained but noted as non-core.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: >
            A reference map of the human binary protein interactome.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23395606
    review:
      summary: >
        Human calcitonin is known to self-aggregate and form amyloid fibrils, which is the basis
        for this annotation. The study identified amyloidogenic determinant peptides in calcitonin
        that mediate self-assembly. This is a real biochemical property of calcitonin but
        represents pathological aggregation rather than a core physiological function.
      action: KEEP_AS_NON_CORE
      reason: >
        Calcitonin self-association and amyloid fibril formation is well-documented and relevant
        to medullary thyroid carcinoma pathology. However, this aggregation-prone behavior is
        not a core physiological function. The primary function is hormone activity via calcitonin
        receptor binding. This annotation should be retained as it documents a real biochemical
        property with clinical implications.
      supported_by:
        - reference_id: PMID:23395606
          supporting_text: >
            Calcitonin is a 32-residue polypeptide hormone, which takes part in calcium metabolism
            in bones. It may form amyloid fibrils. Amyloid fibrils are related with serious
            diseases known as amyloidoses. The amyloid form of calcitonin takes part in medullary
            thyroid carcinoma.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >
        This IEA annotation for extracellular space is redundant with the IBA and IDA annotations
        for the same term. Calcitonin is a secreted hormone found in serum. Keeping multiple
        evidence codes for well-supported localizations is acceptable.
      action: ACCEPT
      reason: >
        Extracellular space localization is correct for calcitonin. Serum calcitonin levels
        have been measured clinically (PMID:18057382). This IEA annotation is redundant with
        IBA and IDA annotations for the same term but is acceptable.
  - term:
      id: GO:0030424
      label: axon
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        This annotation is transferred from rat ortholog based on Ensembl Compara. While the
        CALCA gene produces alpha-CGRP through alternative splicing which is expressed in sensory
        neurons, the calcitonin isoform (P01258) itself is primarily expressed in thyroid C cells.
        This localization may be more relevant to alpha-CGRP (P06881) than to calcitonin.
      action: KEEP_AS_NON_CORE
      reason: >
        Axonal localization is relevant for the alternatively spliced alpha-CGRP isoform expressed
        in sensory neurons, not the calcitonin peptide hormone. The deep research notes that
        alpha-CGRP is expressed in peripheral sensory neurons including trigeminal and dorsal root
        ganglia. However, this annotation applies to the P01258 entry which is the calcitonin
        precursor, not alpha-CGRP. Keep as non-core with the caveat that this may be more relevant
        to the CGRP splice variant.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0042311
      label: vasodilation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Vasodilation is a well-established function of alpha-CGRP, which is produced from the
        CALCA gene by alternative splicing. CGRP is described in the deep research as a potent
        vasodilatory neuropeptide. However, calcitonin itself (the peptide from this UniProt
        entry) is not primarily a vasodilator - that function is specific to CGRP.
      action: KEEP_AS_NON_CORE
      reason: >
        Vasodilation is a core function of alpha-CGRP (P06881) produced by alternative splicing
        of the CALCA gene, not of calcitonin (P01258) itself. The deep research describes CGRP
        as acting at vascular smooth muscle as a potent vasodilator. This annotation likely
        derives from ortholog transfer that does not distinguish between splice variants.
        Keep as non-core to acknowledge the gene-level function while noting it is not the
        primary function of the calcitonin peptide.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0043025
      label: neuronal cell body
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Neuronal cell body localization is more relevant to the alpha-CGRP splice variant that is
        expressed in sensory neurons (trigeminal ganglia, dorsal root ganglia), not to calcitonin
        which is secreted from thyroid C cells. This annotation derives from ortholog transfer.
      action: KEEP_AS_NON_CORE
      reason: >
        The deep research describes alpha-CGRP as expressed in peripheral sensory neurons including
        trigeminal and DRG neurons. Calcitonin (the product of this UniProt entry) is secreted from
        thyroid C cells, not neurons. Keep as non-core to acknowledge that the CALCA gene product
        (as CGRP) is found in neurons while noting this is not the calcitonin peptide function.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0045776
      label: negative regulation of blood pressure
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Blood pressure lowering is a consequence of vasodilation, which is a function of alpha-CGRP
        rather than calcitonin itself. CGRP causes vasodilation and thus reduces blood pressure.
        This annotation derives from ortholog transfer and reflects the gene-level function.
      action: KEEP_AS_NON_CORE
      reason: >
        Negative regulation of blood pressure is secondary to the vasodilatory activity of alpha-CGRP
        produced from the CALCA gene. Calcitonin (P01258) itself is not known for blood pressure
        regulation. Keep as non-core to acknowledge this is a gene-level function via the CGRP
        splice variant.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0045986
      label: negative regulation of smooth muscle contraction
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Relaxation of smooth muscle (vasodilation) is a function of alpha-CGRP acting on vascular
        smooth muscle cells. This is not a primary function of calcitonin. The annotation derives
        from ortholog transfer.
      action: KEEP_AS_NON_CORE
      reason: >
        Smooth muscle relaxation leading to vasodilation is a function of alpha-CGRP, not
        calcitonin. The deep research describes CGRP as acting at vascular smooth muscle. Keep as
        non-core to reflect gene-level function via the CGRP splice variant.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
  - term:
      id: GO:0071356
      label: cellular response to tumor necrosis factor
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        This annotation suggests calcitonin or CGRP is involved in TNF response. While procalcitonin
        (the calcitonin prohormone) is induced during sepsis and inflammation, this annotation
        appears to conflate response to TNF with calcitonin expression regulation.
      action: UNDECIDED
      reason: >
        The relationship between CALCA gene products and TNF response is unclear. Procalcitonin is
        a sepsis biomarker induced during systemic inflammation, but this does not mean calcitonin
        mediates cellular responses to TNF. This annotation from ortholog transfer requires further
        evidence to evaluate. The original reference for the rat ortholog annotation is not
        available for review.
  - term:
      id: GO:0098686
      label: hippocampal mossy fiber to CA3 synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        This highly specific synaptic localization annotation likely derives from rat ortholog
        transfer. CGRP is expressed in sensory neurons and has been detected in various CNS
        regions. However, this specific localization to hippocampal mossy fiber synapses is
        overly specific for the UniProt calcitonin entry.
      action: MARK_AS_OVER_ANNOTATED
      reason: >
        This annotation is too specific without clear supporting evidence for human calcitonin.
        While CGRP has CNS expression, hippocampal mossy fiber synapse localization is a very
        specific claim. The calcitonin peptide (P01258) is primarily a thyroid-derived hormone
        acting on bone. This annotation should be marked as over-annotation.
  - term:
      id: GO:0098992
      label: neuronal dense core vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Neuropeptides like CGRP are stored in and released from dense core vesicles in neurons.
        This annotation is relevant to alpha-CGRP expressed in sensory neurons but not to calcitonin
        secreted from thyroid C cells. Thyroid C cells are neuroendocrine cells that may also use
        dense core vesicles, but this annotation specifies neuronal vesicles.
      action: KEEP_AS_NON_CORE
      reason: >
        Dense core vesicle localization is relevant to neuropeptide secretion. CGRP is released
        from sensory neurons via dense core vesicles. While calcitonin from C cells may also be
        secreted via secretory granules, the annotation specifically refers to neuronal dense core
        vesicles. Keep as non-core to acknowledge CGRP function.
  - term:
      id: GO:1990090
      label: cellular response to nerve growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        This annotation suggests CALCA expression is regulated by NGF or that CALCA products
        mediate responses to NGF. CGRP expression in sensory neurons may be regulated by NGF
        signaling. This annotation derives from ortholog transfer.
      action: UNDECIDED
      reason: >
        The relationship between CALCA/CGRP and NGF response in sensory neurons is plausible
        but the original evidence is not available for review. NGF is known to regulate
        neuropeptide expression in sensory neurons. Without access to the original rat evidence,
        cannot confirm if this applies to the calcitonin peptide (P01258) or is specific to CGRP.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-379044
    review:
      summary: >
        This Reactome annotation for extracellular region derives from the pathway reaction showing
        calcitonin acting as an extracellular ligand for Gs-activating GPCRs. Calcitonin is a
        secreted hormone that acts in the extracellular space.
      action: ACCEPT
      reason: >
        Extracellular region is the correct localization for calcitonin. This TAS annotation from
        Reactome pathway curation is consistent with the IBA and IDA annotations for extracellular
        space. Calcitonin acts as an extracellular ligand for CALCR.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-419843
    review:
      summary: >
        This Reactome annotation derives from the reaction CALCA(83-119) binds CALCR, showing
        calcitonin as an extracellular ligand binding to the calcitonin receptor. Correctly
        places calcitonin in the extracellular compartment.
      action: ACCEPT
      reason: >
        Extracellular region is correct for calcitonin which binds CALCR as an extracellular
        ligand. The Reactome reference specifically models calcitonin-receptor binding.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-744886
    review:
      summary: >
        This Reactome annotation from the Ligand:GPCR:Gs complex dissociation pathway places
        calcitonin in the extracellular region as expected for a secreted hormone ligand.
      action: ACCEPT
      reason: >
        Extracellular region is the correct localization for calcitonin. Redundant with other
        extracellular annotations but consistent with pathway modeling.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-744887
    review:
      summary: >
        This Reactome annotation from the GPCR-Gs binding pathway correctly places calcitonin
        as an extracellular ligand.
      action: ACCEPT
      reason: >
        Extracellular region is correct. Redundant with other annotations for this localization
        but acceptable for pathway context.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9702354
    review:
      summary: >
        This Reactome annotation from the reaction CALCA(83-119) binds CALCA antibodies places
        calcitonin in the extracellular region where it can be bound by therapeutic antibodies.
      action: ACCEPT
      reason: >
        Extracellular region is correct. Calcitonin is a circulating hormone that can be targeted
        by antibodies in the extracellular space.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-976734
    review:
      summary: >
        This annotation from the amyloid fibril pathway places calcitonin in the extracellular
        region where amyloid deposits can form. Calcitonin amyloid is found in medullary thyroid
        carcinoma.
      action: ACCEPT
      reason: >
        Extracellular region is correct. Calcitonin amyloid deposits form extracellularly in
        pathological conditions.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-977136
    review:
      summary: >
        This annotation from the amyloid fibril formation pathway correctly places calcitonin
        in the extracellular region where amyloid precursor proteins can aggregate.
      action: ACCEPT
      reason: >
        Extracellular region is correct for calcitonin. This Reactome pathway models amyloid
        formation from extracellular calcitonin.
  - term:
      id: GO:0005179
      label: hormone activity
    evidence_type: IDA
    original_reference_id: PMID:35324283
    review:
      summary: >
        Hormone activity is a core molecular function of calcitonin. The structural study
        PMID:35324283 demonstrates calcitonin binding to and activating its receptor complexes
        (CTR and AMYR2), which is the mechanistic basis for its hormone activity.
      action: ACCEPT
      reason: >
        Calcitonin is a well-established peptide hormone. The cryo-EM structures show calcitonin
        binding to CTR and AMYR complexes in active conformations, directly demonstrating its
        ability to act as a hormone ligand.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:35324283
          supporting_text: >
            We determined the structure and dynamics of active AMYRs with amylin, AMY1R with
            salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
  - term:
      id: GO:0097646
      label: calcitonin family receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:35324283
    review:
      summary: >
        Calcitonin is the prototypical ligand of the calcitonin receptor signaling pathway.
        The structural study demonstrates calcitonin bound to CTR in active G protein-coupled
        conformations, directly supporting its role in this signaling pathway.
      action: ACCEPT
      reason: >
        Calcitonin family receptor signaling pathway is a core biological process for calcitonin.
        The cryo-EM structures in PMID:35324283 show calcitonin bound to CTR-G protein complexes,
        providing direct structural evidence for calcitonin activating this pathway.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:35324283
          supporting_text: >
            We determined the structure and dynamics of active AMYRs with amylin, AMY1R with
            salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
  - term:
      id: GO:0150060
      label: amylin receptor 2 signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:35324283
    review:
      summary: >
        UniProt explicitly states that calcitonin function is mediated by the CALCR-RAMP2 (AMYR2)
        receptor complex, and the structural study shows calcitonin bound to AMY2R. Calcitonin
        can signal through amylin receptor 2 in addition to CTR.
      action: ACCEPT
      reason: >
        The structural study PMID:35324283 directly demonstrates calcitonin bound to AMY2R
        (CTR+RAMP2) in active conformations. UniProt annotation also notes that calcitonin
        function is mediated by CALCR-RAMP2 complex. This is a legitimate signaling pathway
        for calcitonin.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:35324283
          supporting_text: >
            Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and
            one of three receptor activity-modifying proteins (RAMPs), AMY1R, AMY2R, and AMY3R.
  - term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:11014233
    review:
      summary: >
        The study demonstrates that calcitonin treatment activates adenylate cyclase in human
        osteoclast-like cells. Calcitonin-sensitive adenylate cyclase responsiveness was measured
        to track receptor function and desensitization.
      action: ACCEPT
      reason: >
        Adenylate cyclase activation is a core signaling mechanism for calcitonin. The study
        directly measures CT-sensitive adenylate cyclase responsiveness in human osteoclasts,
        providing experimental evidence for this pathway.
      supported_by:
        - reference_id: PMID:11014233
          supporting_text: >
            The reduced specific binding, CTR messenger RNA levels, and CT-sensitive adenylate
            cyclase responsiveness returned to the control levels by 96 h after removal of CT.
  - term:
      id: GO:0002548
      label: monocyte chemotaxis
    evidence_type: IDA
    original_reference_id: PMID:15248232
    review:
      summary: >
        This publication studies RANKL-induced monocyte chemotaxis, not calcitonin. The study
        demonstrates that RANKL stimulates monocyte migration via RANK. Calcitonin is not
        directly studied in this paper; this appears to be an erroneous annotation.
      action: REMOVE
      reason: >
        PMID:15248232 studies RANKL (TNFSF11) and its receptor RANK (TNFRSF11A), not calcitonin
        (CALCA). The abstract clearly states that RANKL stimulates monocyte chemotaxis via RANK.
        There is no evidence in this paper for calcitonin involvement in monocyte chemotaxis.
        This annotation should be removed as it appears to be incorrectly attributed to CALCA.
      supported_by:
        - reference_id: PMID:15248232
          supporting_text: >
            RANKL significantly stimulated monocyte chemotaxis via activation of
            phosphatidylinositol 3-kinase, phosphodiesterase, and Src kinase.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IDA
    original_reference_id: PMID:18057382
    review:
      summary: >
        This study measures serum calcitonin levels using immunoassays, directly demonstrating
        that calcitonin is present in the extracellular space (serum/blood). This is direct
        experimental evidence for extracellular localization.
      action: ACCEPT
      reason: >
        The study measured serum calcitonin concentrations in healthy subjects using multiple
        immunoassays, providing direct experimental evidence that calcitonin is secreted into
        and present in the extracellular space (blood/serum).
      supported_by:
        - reference_id: PMID:18057382
          supporting_text: >
            The objective of this study was to re-evaluate the adult C(T) reference values
            determined by five different immunoassays and by introducing criteria for selecting
            control subjects.
  - term:
      id: GO:0007204
      label: positive regulation of cytosolic calcium ion concentration
    evidence_type: IDA
    original_reference_id: PMID:17983652
    review:
      summary: >
        The study shows that calcitonin treatment causes rapid increases in cytosolic calcium
        levels in endometrial epithelial cells. This calcium mobilization is part of the
        signaling mechanism by which calcitonin promotes trophoblast outgrowth.
      action: ACCEPT
      reason: >
        The study directly demonstrates that calcitonin exposure causes rapid increase in
        cytosolic calcium in endometrial epithelial cells. This is direct experimental evidence
        for calcitonin-induced calcium mobilization. Note this is distinct from the IBA
        annotation for GO:0051480 (regulation of cytosolic calcium ion concentration) which
        is about systemic calcium homeostasis.
      supported_by:
        - reference_id: PMID:17983652
          supporting_text: >
            Cytosolic calcium (Ca(2+)) levels in EEC increased rapidly upon exposure to
            calcitonin, and blockade of Ca(2+) release by BAPTA-AM effectively prevented the
            promoting effect of calcitonin on trophoblast expansion on EEC.
  - term:
      id: GO:0007566
      label: embryo implantation
    evidence_type: IDA
    original_reference_id: PMID:17983652
    review:
      summary: >
        The study demonstrates that calcitonin promotes trophoblast cell outgrowth on endometrial
        epithelial cells, suggesting a role in facilitating embryo implantation. However, this is
        an in vitro cell culture study and embryo implantation is a complex organismal process.
      action: KEEP_AS_NON_CORE
      reason: >
        While the study provides evidence that calcitonin facilitates trophoblast-endometrial
        interaction in vitro, embryo implantation is not a core function of calcitonin. The
        primary function of calcitonin is calcium homeostasis and bone resorption inhibition.
        The role in implantation is a secondary/pleiotropic effect. Keep as non-core.
      supported_by:
        - reference_id: PMID:17983652
          supporting_text: >
            calcitonin promotes trophoblastic displacement of EEC through calcium mobilization
            and PKC activation, thereby facilitating embryo implantation.
  - term:
      id: GO:0032147
      label: activation of protein kinase activity
    evidence_type: IDA
    original_reference_id: PMID:17983652
    review:
      summary: >
        The study shows that calcitonin activates protein kinase C (PKC) in endometrial epithelial
        cells as part of its signaling mechanism. PKC activation is downstream of calcium
        mobilization induced by calcitonin.
      action: ACCEPT
      reason: >
        PKC activation is part of the calcitonin signaling mechanism demonstrated in this study.
        This is consistent with the broader understanding of calcitonin receptor signaling through
        both adenylate cyclase and PKC pathways.
      supported_by:
        - reference_id: PMID:17983652
          supporting_text: >
            The Ca(2+)-dependent protein kinase C (PKC) was also activated in EEC after calcitonin
            treatment, and the PKC inhibitors staurosporine and calphostin C could completely
            abolish calcitonin-induced augmentation of trophoblast expansion on EEC.
  - term:
      id: GO:0045779
      label: negative regulation of bone resorption
    evidence_type: IDA
    original_reference_id: PMID:17241109
    review:
      summary: >
        Inhibition of bone resorption is a core physiological function of calcitonin. The study
        directly demonstrates that calcitonin dose-dependently inhibits bone resorption by human
        osteoclasts in vitro. This is the classical pharmacological action of calcitonin.
      action: ACCEPT
      reason: >
        Negative regulation of bone resorption is a core function of calcitonin. The study uses
        a functional assay measuring CTX-I release (collagen degradation product) and shows
        calcitonin dose-dependently inhibits resorption. This is consistent with the deep research
        noting that calcitonin rapidly inhibits osteoclast activity.
      additional_reference_ids:
        - file:human/CALCA/CALCA-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:17241109
          supporting_text: >
            CT (calcitonin) dose-dependently inhibited bone resorption, whereas PTH (parathyroid
            hormone), IL (interleukin)-1, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-8,
            VEGF (vascular endothelial growth factor), MCP-1 (monocyte chemoattractant protein-1),
            MIP-1gamma (macrophage inflammatory protein-1gamma), IFN (interferon)-gamma and
            dibutyryl cGMP had no significant effect.
  - term:
      id: GO:0031716
      label: calcitonin receptor binding
    evidence_type: IPI
    original_reference_id: PMID:8078488
    review:
      summary: >
        This study cloned and characterized the human calcitonin receptor and demonstrated
        calcitonin binding to the recombinant receptor with high affinity. Binding studies
        directly demonstrate the physical interaction between calcitonin and its receptor.
      action: ACCEPT
      reason: >
        Calcitonin receptor binding is a core molecular function. The study directly measures
        calcitonin binding to cloned human CTR and demonstrates high affinity binding. This is
        experimental evidence for the primary ligand-receptor interaction.
      supported_by:
        - reference_id: PMID:8078488
          supporting_text: >
            Like the endogenous T47D receptor, the recombinant receptor has an equally high
            affinity for salmon and porcine calcitonin but a 3-4-fold lower affinity for human
            calcitonin.
  - term:
      id: GO:0031716
      label: calcitonin receptor binding
    evidence_type: IPI
    original_reference_id: PMID:8940110
    review:
      summary: >
        This study characterized calcitonin binding to different CTR isoforms including a novel
        splice variant. Binding studies with salmon and human calcitonin demonstrate the
        physical interaction with receptor isoforms.
      action: ACCEPT
      reason: >
        The study directly measures calcitonin binding to CTR isoforms, demonstrating the
        ligand-receptor interaction. This is experimental evidence supporting calcitonin
        receptor binding as a core molecular function.
      supported_by:
        - reference_id: PMID:8940110
          supporting_text: >
            Deletion of the residues in the seventh transmembrane domain in CTRDeltae13 reduced
            the binding affinity for salmon and human calcitonin by more than 10-fold and
            approximately 2-fold, respectively, resulting in a receptor that failed to
            discriminate between the two forms of calcitonin.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:11014233
    review:
      summary: >
        The study shows that calcitonin treatment reduces CTR mRNA expression levels in
        osteoclasts, indicating negative regulation of transcription. This is part of the
        receptor down-regulation mechanism.
      action: KEEP_AS_NON_CORE
      reason: >
        The study demonstrates that calcitonin treatment reduces calcitonin receptor (CTR)
        mRNA levels, which is a form of negative transcriptional regulation. However, this
        is a secondary effect related to receptor desensitization rather than a primary
        function of calcitonin. Keep as non-core.
      supported_by:
        - reference_id: PMID:11014233
          supporting_text: >
            Treatment with sCT reduced CTR messenger RNA expression, suggesting that CTR
            down-regulation is, at least partly, attributable to an inhibition of de novo
            CTR synthesis.
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:11014233
    title: Calcitonin receptor regulation and responsiveness to calcitonin in
      human osteoclast-like cells prepared in vitro using receptor activator of
      nuclear factor-kappaB ligand and macrophage colony-stimulating factor.
    findings: []
  - id: PMID:15248232
    title: Expression and function of RANK in human monocyte chemotaxis.
    findings: []
  - id: PMID:17241109
    title: Regulation and enzymatic basis of bone resorption by human
      osteoclasts.
    findings: []
  - id: PMID:17689535
    title: The interaction between endogenous calcineurin and the plasma
      membrane calcium-dependent ATPase is isoform specific in breast cancer
      cells.
    findings: []
  - id: PMID:17983652
    title: 'Calcitonin promotes outgrowth of trophoblast cells on endometrial epithelial
      cells: involvement of calcium mobilization and protein kinase C activation.'
    findings: []
  - id: PMID:18057382
    title: 'Reference range of serum calcitonin levels in humans: influence of calcitonin
      assays, sex, age, and cigarette smoking.'
    findings: []
  - id: PMID:23395606
    title: Identification of a novel 'aggregation-prone'/'amyloidogenic
      determinant' peptide in the sequence of the highly amyloidogenic human
      calcitonin.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:35324283
    title: A structural basis for amylin receptor phenotype.
    findings: []
  - id: PMID:8078488
    title: Cloning and characterization of an abundant subtype of the human
      calcitonin receptor.
    findings: []
  - id: PMID:8940110
    title: The deletion of 14 amino acids in the seventh transmembrane domain of
      a naturally occurring calcitonin receptor isoform alters ligand binding
      and selectively abolishes coupling to phospholipase C.
    findings: []
  - id: Reactome:R-HSA-379044
    title: Liganded Gs-activating GPCR acts as a GEF for Gs
    findings: []
  - id: Reactome:R-HSA-419843
    title: CALCA(83-119) binds CALCR
    findings: []
  - id: Reactome:R-HSA-744886
    title: The Ligand:GPCR:Gs complex dissociates
    findings: []
  - id: Reactome:R-HSA-744887
    title: Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs
    findings: []
  - id: Reactome:R-HSA-9702354
    title: CALCA(83-119) binds CALCA antibodies
    findings: []
  - id: Reactome:R-HSA-976734
    title: Amyloid fibrils have additional components
    findings: []
  - id: Reactome:R-HSA-977136
    title: Amyloid precursor proteins form ordered fibrils
    findings: []
core_functions:
  - molecular_function:
      id: GO:0031716
      label: calcitonin receptor binding
    description: >
      Calcitonin receptor binding is the primary molecular function of calcitonin. The peptide
      hormone binds with high affinity to the calcitonin receptor (CALCR), a class B GPCR, to
      initiate downstream signaling. Structural studies have determined cryo-EM structures of
      calcitonin bound to CTR and amylin receptor complexes (PMID:35324283).
    directly_involved_in:
      - id: GO:0097646
        label: calcitonin family receptor signaling pathway
      - id: GO:0045779
        label: negative regulation of bone resorption
      - id: GO:0051480
        label: regulation of cytosolic calcium ion concentration
    locations:
      - id: GO:0005576
        label: extracellular region
    supported_by:
      - reference_id: PMID:35324283
        supporting_text: >
          We determined the structure and dynamics of active AMYRs with amylin, AMY1R with
          salmon CT (sCT), AMY2R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT.
      - reference_id: PMID:8078488
        supporting_text: >
          Like the endogenous T47D receptor, the recombinant receptor has an equally high
          affinity for salmon and porcine calcitonin but a 3-4-fold lower affinity for human
          calcitonin.
  - molecular_function:
      id: GO:0005179
      label: hormone activity
    description: >
      Calcitonin is a peptide hormone secreted by thyroid parafollicular C cells. It acts as a
      classical hormone, traveling through the bloodstream to target tissues (primarily bone)
      where it binds its receptor to exert calciotropic effects. Calcitonin causes a rapid
      drop in blood calcium by inhibiting osteoclast-mediated bone resorption.
    directly_involved_in:
      - id: GO:0007189
        label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    locations:
      - id: GO:0005576
        label: extracellular region
    anatomical_locations:
      - id: UBERON:0002046
        label: thyroid gland
    supported_by:
      - reference_id: PMID:18057382
        supporting_text: >
          The objective of this study was to re-evaluate the adult C(T) reference values
          determined by five different immunoassays and by introducing criteria for selecting
          control subjects.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Citations

📄 View Raw YAML