Calcitonin

CALCA
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 2JXZ,%%s1LS7
Identifiers
Aliases	CALCA, CALC1, CGRP, CGRP-I, CGRP1, CT, KC, PCT, calcitonin related polypeptide alpha, Calcitonin
External IDs	OMIM: 114130 HomoloGene: 88401 GeneCards: CALCA
Gene ontology Molecular function • hormone activity • calcitonin receptor binding • protein binding • identical protein binding • receptor binding • protein complex binding Cellular component • cytoplasm • intracellular • extracellular region • axon • terminal bouton • neuronal cell body • neuron projection • Q40260 • extracellular space Biological process • cellular protein metabolic process • cellular response to nerve growth factor stimulus • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway • positive regulation of adenylate cyclase activity • negative regulation of smooth muscle contraction • regulation of heart contraction • adenylate cyclase-activating G-protein coupled receptor signaling pathway • monocyte chemotaxis • negative regulation of blood pressure • positive regulation of cytosolic calcium ion concentration • cellular response to tumor necrosis factor • aging • vasodilation • cellular calcium ion homeostasis • response to heat • negative regulation of neurological system process • positive regulation of ossification • activation of adenylate cyclase activity • regulation of heart rate • detection of temperature stimulus involved in sensory perception of pain • negative regulation of ossification • response to pain • artery vasodilation involved in baroreceptor response to increased systemic arterial blood pressure • feeding behavior • inflammatory response • neuropeptide signaling pathway • negative regulation of transcription, DNA-templated • activation of protein kinase activity • embryo implantation • negative regulation of bone resorption • leukocyte cell-cell adhesion • positive regulation of cAMP biosynthetic process • G-protein coupled receptor internalization • positive regulation of interleukin-1 alpha production • response to yeast • regulation of cytosolic calcium ion concentration • negative regulation of osteoclast differentiation • cell-cell signaling • antibacterial humoral response • positive regulation of macrophage differentiation • receptor internalization • regulation of blood pressure • protein phosphorylation • vasculature development • defense response to Gram-negative bacterium • endothelial cell proliferation • positive regulation of interleukin-8 production • neurological system process involved in regulation of systemic arterial blood pressure • negative regulation of calcium ion transport into cytosol • innate immune response • endothelial cell migration • antifungal humoral response • defense response to Gram-positive bacterium • antimicrobial humoral immune response mediated by antimicrobial peptide • positive regulation of blood vessel diameter Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	796	n/a
Ensembl	ENSG00000110680	n/a
UniProt	P01258 P06881	n/a
RefSeq (mRNA)	NM_001033952 NM_001033953 NM_001741	n/a
RefSeq (protein)	NP_001029124.1 NP_001732.1 NP_001029125.1	n/a
Location (UCSC)	n/a	n/a
PubMed search	[1]	n/a
Wikidata
View/Edit Human

Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced in humans primarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimopharyngeal body.^[2] It acts to reduce blood calcium (Ca²⁺), opposing the effects of parathyroid hormone (PTH).^[3]

Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.^[4] It belongs to the calcitonin-like protein family.

Biosynthesis and regulation

Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA). The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.

Secretion of calcitonin is stimulated by:

• an increase in serum [Ca²⁺]^[5]
• gastrin and pentagastrin.^[6]

Effects

The hormone participates in calcium (Ca²⁺) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH).

More specifically, calcitonin lowers blood Ca²⁺ levels in two ways:

• Major effect: Inhibits osteoclast activity in bones^[7]
• Minor effect: Inhibits renal tubular cell reabsorption of Ca²⁺ and phosphate, allowing them to be excreted in the urine^[8][9]

High concentrations of calcitonin may be able to increase urinary excretion of calcium and phosphate, via actions on the kidney tubules.^[10] However, this is a minor effect with no physiological significance in humans. It is also a short-lived effect because the kidneys become resistant to calcitonin, as demonstrated by the kidney's unaffected excretion of calcium in patients with thyroid tumors that secrete excessive calcitonin.^[11]

In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation. The protective mechanisms include the direct inhibition of bone resorption and the indirect effect through the inhibition of the release of prolactin from the pituitary gland. The reason provided is that prolactin induces the release of PTH related peptide which enhances bone resorption, but is still under investigation., ^[12][13][14]

Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca²⁺. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.

Calcitonin lowers blood calcium and phosphorus mainly through its inhibition of osteoclasts. Osteoblasts do not have calcitonin receptors and are therefore not directly affected by calcitonin levels. However, since bone resorption and bone formation are coupled processes, eventually calcitonin's inhibition of osteoclastic activity leads to decreased osteoblastic activity (as an indirect effect).^[11]

Receptor

The calcitonin receptor, found on osteoclasts,^[15] and in the kidney and regions of the brain, is a G protein-coupled receptor, which is coupled by G_s to adenylate cyclase and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.

Discovery

Calcitonin was purified in 1962 by Copp and Cheney.^[16] While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland.^[17]

Medical Significance

A malignancy of the parafollicular cells, i.e. Medullary thyroid cancer, typically produces an elevated serum calcitonin level.

Pharmacology

Salmon calcitonin is used for the treatment of:

• Postmenopausal osteoporosis
• Hypercalcaemia
• Paget's disease
• Bone metastases
• Phantom limb pain^[18]

It has been investigated as a possible non-operative treatment for spinal stenosis.^[19]

The following information is from the UK Electronic Medicines Compendium^[20]

General characteristics of the active substance

Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.

Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).

Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.

Characteristics in patients

There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.

Preclinical safety data

Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.

An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance.^[21] Salmon calcitonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.

Pharmaceutical manufacture

Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.^[20]

Uses of calcitonin

Treatments

Calcitonin affecting the spine.

Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.^[22] In a recent clinical study, subcutaneous injections of calcitonin have reduced the incidence of fractures and reduced the decrease in bone mass in women with type 2 diabetes complicated with osteoporosis.^[23]

Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.^[24] However no further work on this potential application of calcitonin has been reported.

Diagnostics

It may be used diagnostically as a tumor marker for medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g., lymph nodes that are swollen) to establish whether they are metastases of the original cancer.

Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:^[25]

• females: 5 ng/L or pg/mL
• males: 12 ng/L or pg/mL
• children under 6 months of age: 40 ng/L or pg/mL
• children between 6 months and 3 years of age: 15 ng/L or pg/mL

When over 3 years of age, adult cutoffs may be used

Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, Nonthyroidal oat cell carcinoma, Nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.^[26]

Structure

Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix.^[27] Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.^[28]

The following are the amino acid sequences of salmon and human calcitonin:

• salmon:

      Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro

• human:

      Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro

Compared to salmon calcitonin, human calcitonin differs at 16 residues.

See also

• Procalcitonin

References

Further reading

External links

• The Calcitonin Protein
• Calcitonin at the US National Library of Medicine Medical Subject Headings (MeSH)