The structural formula

UV – range

IR – spectrum

Links

Calcitonin-related polypeptide alpha
NMR solution structure of salmon calcitonin in SDS micelles.[1]
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	CALCA ; CALC1; CGRP; CGRP-I; CGRP1; CT; KC
External IDs	OMIM: 114130 MGI: 2151253HomoloGene: 88401 ChEMBL: 5293GeneCards: CALCA Gene
[show]Gene ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	796	12310
Ensembl	ENSG00000110680	ENSMUSG00000030669
UniProt	P01258	P70160
RefSeq (mRNA)	NM_001033952	NM_001033954
RefSeq (protein)	NP_001029124	NP_001029126
Location (UCSC)	Chr 11: 14.99 – 14.99 Mb	Chr 7: 114.63 – 114.64 Mb
PubMedsearch	[1]	[2]

 

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]
• Stimulates osteoblastic activity in bones. ^[8]
• Inhibits renal tubular cell reabsorption of Ca²⁺ allowing it to be excreted in the urine^[9][10]

However, effects of calcitonin that mirror those of PTH include the following:

• Inhibits phosphate reabsorption by the kidney tubules^[11]

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

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-cellsof 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, 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. 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., lymph nodes that are swollen) 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

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.^[21]

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.^[22]

The following are the amino acid sequences of salmon and human calcitonin:^[23]

• 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.

Description: Cellular and molecular coordination of tissues which secrete chemical compounds to regulate growth, reproduction, metabolism, and ion homeostasis.

 

 

 

 

References

Further reading

External links

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

 

 

 

 

 

Literature References: 

Calcium regulating hormone secreted from the mammalian thyroid gland and in non-mammalian species from the ultimobranchial gland. Postulation of a plasma-calcium lowering substance: Copp et al., Endocrinology 70, 638 (1962).

 

Recognition as a hormone: Hirsch et al., ibid. 73, 244 (1963); of thyroid origin: Foster et al., Nature 202, 1303 (1964).

 

Over-all action is to oppose the bone and renal effects of parathyroid hormone, q.v.; inhibits bone resorption of Ca2+, with accompanying hypocalcemia and hypophosphatemia and decreased urinary Ca2+ concentrations. Also abolishes the osteolytic effect of toxic doses of vitamins A and D. Calcitonin is highly active biologically, e.g. 50 mg/min infused into a 100 g rat leads to a significant (1 mg/100 ml) decrease in the concn of the plasma calcium within 60 min (together with a corresponding fall in plasma phosphate). Activity is destroyed by trypsin, chymotrypsin, pepsin, polyphenol oxidase; also by hydrogen peroxide oxidation, photooxidation, and treatment with N-bromosuccinimide. Calcitonin structures are single polypeptide chains containing 32 amino acid residues. Structure of porcine: Neher et al., Helv. Chim. Acta 51, 917 (1968); Potts et al., Proc. Natl. Acad. Sci. USA 59, 1321 (1968); Bellet al., J. Am. Chem. Soc. 90, 2704 (1968); eidem, Biochemistry 9, 1665 (1970).

 

Synthesis of porcine: Rittel et al., Helv. Chim. Acta 51, 924 (1968); Guttmann et al., ibid. 1155.

 

Isoln of human calcitonin from non-pathological thyroid glands: Haymovits, Rosen, Endocrinology 81, 993 (1967); from medullary carcinoma of the thyroid: Neher et al., Nature 220, 984 (1968); Helv. Chim. Acta 51, 1738 (1968); Neher, Riniker, DE 1929957 (1970 to Ciba), C.A. 73, 28902b (1970).

 

Structure of human: Neher et al., Helv. Chim. Acta 51, 1900 (1968). Synthesis of human: Sieber et al., ibid. 2057; J. Hirt et al., Rec. Trav. Chim. 98, 143 (1979).

 

Biosynthetic studies: J. W. Jacobs et al., J. Biol. Chem. 254, 10600 (1979); S. G. Amara et al., ibid. 255, 2645 (1980).

 

Amino acid sequence differs among mammalian species, salmon calcitonin showing a marked difference from that of the higher vertebrae as well as a more potent biological activity. Mechanism of action: E. M. Brown, G. D. Aurbach, Vitam. Horm. 38, 236 (1980). Anorectic activity in rats: W. J. Freed et al., Science 206, 850 (1979).

 

Growth inhibition of human breast cancer cells in vitro: Y. Iwasaki et al., Biochem. Biophys. Res. Commun. 110, 235 (1983).

Review of early literature: Munson, Hirsch, Clin. Orthop. 49, 209 (1966).

 

Review of isoln, structure, synthesis: Behrens, Grinnan, Annu. Rev. Biochem. 38, 83 (1969); Potts et al., Vitam. Horm. 29,41 (1971).

 

Comprehensive review: Calcitonin, Proc. Symp. on Thyrocalcitonin and the C Cells, S. Taylor, Ed. (Springer-Verlag, New York, 1968); Foster et al., ”Calcitonin” in Clinics in Endocrinology and Metabolism, I. MacIntyre, Ed. (W. B. Saunders, Philadelphia, 1972) pp 93-124.

 

Review of pharmacology and therapeutic use: J. C. Stevenson, I. M. A. Evans, Drugs 21, 257-272 (1981).

 

 

 

Derivative Type: Calcitonin, porcine

CAS Registry Number: 12321-44-7

Trademarks: Calcitar(e) (RPR); Staporos (Cassenne)

 

Derivative Type: Calcitonin, human synthetic

CAS Registry Number: 21215-62-3

Trademarks: Cibacalcin (Novartis)

 

Derivative Type: Calcitonin, salmon synthetic

CAS Registry Number: 47931-85-1

Additional Names: Salcatonin

Trademarks: Calciben (Firma); Calcimar (RPR); Calsyn (RPR); Calsynar (RPR); Catonin (Magis); Karil (Novartis); Miacalcic (Novartis); Miacalcin (Novartis); Miadenil (Francia); Osteocalcin (Tosi); Prontocalcin (Domp?; Rulicalcin (HMR); Salmotonin (Yamanouchi); Stalcin (Locatelli); Tonocalcin (Searle)

Literature References: Clinical trial in postmenopausal osteoporosis: C. H. Chesnut et al., Am. J. Med. 109, 267 (2000). LC determn in biological fluids: M. Aguiar et al., J. Chromatogr. B 818, 301 (2005).

Properties: See also Elcatonin.

 

eel

cas   57014-02-5