calcitonin

Calcitonin-related polypeptide alpha
NMR solution structure of salmon calcitonin in SDS micelles.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2JXZ
Identifiers
Symbols	CALCA; CALC1; CGRP; CGRP-I; CGRP1; CT; KC
External IDs	OMIM: 114130 MGI: 2151253 HomoloGene: 105261 GeneCards: CALCA Gene
Gene Ontology Molecular function • receptor binding • hormone activity • protein binding • calcitonin receptor binding • protein complex binding Cellular component • extracellular region • extracellular space • intracellular • nucleus • cytoplasm • cytoplasm • axon • neuronal cell body • terminal button Biological process • endothelial cell proliferation • vasculature development • neurological system process involved in regulation of systemic arterial blood pressure • vasodilation of artery involved in baroreceptor response to increased systemic arterial blood pressure • regulation of heart rate • G-protein coupled receptor internalization • monocyte chemotaxis • protein phosphorylation • cellular calcium ion homeostasis • leukocyte cell-cell adhesion • activation of adenylate cyclase activity by G-protein signaling pathway • activation of adenylate cyclase activity • elevation of cytosolic calcium ion concentration • neuropeptide signaling pathway • cell-cell signaling • embryo implantation • aging • feeding behavior • regulation of blood pressure • response to heat • negative regulation of calcium ion transport into cytosol • negative regulation of ossification • positive regulation of cAMP biosynthetic process • receptor internalization • negative regulation of neurological system process • activation of protein kinase activity • positive regulation of interleukin-1 alpha production • positive regulation of interleukin-8 production • endothelial cell migration • positive regulation of macrophage differentiation • negative regulation of osteoclast differentiation • positive regulation of adenylate cyclase activity • negative regulation of blood pressure • negative regulation of blood pressure • positive regulation of ossification • negative regulation of bone resorption • positive regulation of cell adhesion • negative regulation of transcription, DNA-dependent • positive regulation of vasodilation • negative regulation of smooth muscle contraction • response to pain • regulation of inflammatory response • detection of temperature stimulus involved in sensory perception of pain • cytosolic calcium ion homeostasis • elevation of cytosolic calcium ion concentration involved in G-protein signaling coupled to IP3 second messenger Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	796	12310
Ensembl	ENSG00000110680	ENSMUSG00000030669
UniProt	P01258	Q99JA0
RefSeq (mRNA)	NM_001033952.2	NM_001033954
RefSeq (protein)	NP_001029124.1	NP_001029126
Location (UCSC)	Chr 11: 14.99 – 14.99 Mb	Chr 7: 114.42 – 114.43 Mb
PubMed search	[1]	[2]
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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 ultimobranchial 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 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 three ways:

• Inhibits Ca²⁺ absorption by the intestines^[7]
• Inhibits osteoclast activity in bones^[8]
• Inhibits renal tubular cell reabsorption of Ca²⁺ allowing it to be secreted in the urine^[9]

• Vitamin D regulation

In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation

While calcitonin is the antipode of parathyroid hormone (PTH) in those actions, it is not dissimilar from PTH in its effect on electrolyte reabsorption in the kidneys. Namely, calcitonin:

• Inhibits phosphate reabsorption by the kidney tubules^[10]
• Decreases tubular reabsorption of Ca²⁺, leading to increased rates of its loss in urine.^[11]

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.

Receptor

The calcitonin receptor, found on osteoclasts,^[12] and in 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.^[13] 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.^[14]

Pharmacology

Salmon calcitonin is used for the treatment of:

• Postmenopausal osteoporosis
• Hypercalcaemia
• Paget's disease
• Bone metastases
• Phantom limb pain^[15]

It has been investigated as a possible non-operative treatment for spinal stenosis.^[16]

The following information is from the UK Electronic Medicines Compendium^[17]

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 and vomiting.

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.^{[citation needed]} 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.^[17]

Uses of calcitonin

Treatments

Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.

Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.

This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”^[18]

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.^[19] 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., swollen lymph nodes) to establish whether they are metastasis 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:^[20]

• 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

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.^[1] 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.^[21]

The following are the amino acid sequences of salmon and human calcitonin:^[22]

• 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
• MeSH Calcitonin