Calcitonin

Calcitonin/calcitonin-related polypeptide, alpha
Identifiers
Symbol(s)	CALCA; CALC1; CGRP; CGRP-I; CGRP1; CT; KC; MGC126648
External IDs	OMIM: 114130 MGI: 2151253 HomoloGene: 1319
Gene Ontology Molecular Function: • hormone activity Cellular Component: • extracellular region • extracellular space • soluble fraction • endoplasmic reticulum Biological Process: • skeletal development • G-protein signaling, coupled to cAMP nucleotide second messenger • adenylate cyclase activation • phospholipase C activation • elevation of cytosolic calcium ion concentration • cell-cell signaling • blood pressure regulation
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	796	12310
Ensembl	ENSG00000110680	ENSMUSG00000030669
Uniprot	P01258	Q99JA0
Refseq	NM_001033952 (mRNA) NP_001029124 (protein)	NM_001033954 (mRNA) NP_001029126 (protein)
Location	Chr 11: 14.94 - 14.95 Mb	Chr 7: 114.42 - 114.43 Mb
Pubmed search	[1]	[2]

Calcitonin is a 32 amino acid polypeptide hormone that is involved in calcium regulation in vertebrates. It acts to reduce blood calcium (Ca²⁺) levels, working in opposite but complementary ways to the effects of the 84 amino acid parathyroid hormone (PTH), which acts to increase the concentration of calcium in the blood.

Calcitonin has been found in a diversity of fish, reptiles, birds, and mammals, including humans. In humans, calcitonin is produced by the cells of the thyroid, while in many submammalian species it is produced by a distinct ultimobranchial body, a small [[organ (anatomy)|organ found in the neck region (Ogle and Costoff 1999). The amino acid sequence shows differences between various groups, with salmon calcitonin, for example, differing in three amino acids from eel calcitonin (Noda and Narita 1976) and by 16 amino acids from that of humans (Ogle and Costoff 1999). Interestingly, calcitonin from salmon ultimobranchial bodies exhibits greater biological activity and longer half-life in humans than even human calcitonin, such as in arresting bone resorption, and itis often used in clinical medicine for treating various ailments, such as metabolic bone disease (Ogle and Costoff 1999).

The opposite and yet complementary effects of calcitonin relative to parathyroid hormone is reflective of the philosophy of Yin and Yang. Just as Yin and Yang are opposing, yet complementary and interdependent forces, calcitonin and parathyroid hormone complement each other and are both necessary to create overall harmony and balance in the living organism.

Chemistry and formation in body

Calcitoni is a small peptide of 32 amino acids and a molecular weight of 3500, with a unique disulfide bridge between amino acids one and seven (Ogle and Costoff 1999). Species differences in amino acid sequences are small. For example, eel calcitonin has the following sequence:

• 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-Asp-Val-Gly-Ala-Gly-Thr-Pro.

This differs only in the 26th, 27th, and 29th positions in comparison with salmon calcitonin I:

• 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 calcitonin differs in 16 positions from salmon calcitonin:

• 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

In humans, calcitonin is produced by the parafollicular cells (also known as C-cells) that surround the thyroid follicular cells in the thyroid, while in many other submammalian species it is produced by a distinct ultimobranchial body, a small [[organ (anatomy)|organ found in the neck region (Ogle and Costoff 1999). In humans, the ultimobranchial body is an embryological structure that gives rise to the calcitonin-producing cells, or parafollicular cells (also called clear cells) —of the thyroid gland.

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. CT is cleaved from a prohormone that also contains two other peptides, katacalcin and calcitonin gene-related peptide (CGRP). These peptides are secreted 1:1 with CT and are therefore found in equimolar ratio with CT in the circulation. Some evidence suggests that CGRP is a vasodilator. CT and CGRP have been isolated from other organs, including the pituitary, suggesting that they may have other functions besides lowering plasma calcium.

Physiology and actions

Calcitonin participates in calcium (Ca²⁺) and phosphorus metabolism. In many ways, calcitonin has the counter effects of parathyroid hormone (PTH).

To be specific, calcitonin reduces blood Ca²⁺ levels in three ways:

• Decreasing Ca²⁺ absorption by the intestines
• Decreasing osteoclast activity in bones
• Decreasing Ca²⁺ and phosphate reabsorption by the kidney tubules

Its actions, in a broad sense, are:

• Bone mineral metabolism:

- Prevent postprandial hypercalcemia resulting from absorption of Ca²⁺ from foods during a meal

- Promote mineralization of skeletal bone

- Protect against Ca²⁺ loss from skeleton during periods of Ca²⁺ stress such as pregnancy and lactation

• Vitamin D regulation
• A satiety hormone:

- Inhibit food intake in rats and monkeys

- May have CNS action involving the regulation of feeding and appetite

Its importance in humans has not been as well established as its importance in other animals.

The calcitonin receptor, found primarily on osteoclasts, is a G protein-coupled receptor, which is coupled by G_s to adenylyl cyclase and thereby to the generation of cAMP in target cells.

salmon calcitonin has been shown to be considerably more effective in arresting bone resorption than human forms of calcitonin. S highest hormal activty among calcitonis so far isolaged (Noda and Narita 1976).

note:Parathyroid hormone (PTH), or parathormone, is secreted by the parathyroid glands as a polypeptide containing 84 amino acids. It acts to increase the concentration of calcium (Ca²⁺) in the blood, whereas calcitonin (a hormone produced by the parafollicular cells (C cells) of the thyroid gland) acts to decrease calcium concentration. PTH acts to increase the concentration of calcium in the blood by acting upon parathyroid hormone receptor in three parts of the body:

History

Calcitonin was purified in 1962 by Copp and Cheney. 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.

Pharmacology

Salmon calcitonin is used for the treatment of:

• Postmenopausal osteoporosis
• Hypercalcaemia
• Paget's disease
• Bone metastases
• Phantom limb pain

The following information is from the UK Electronic Medicines Compendium

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. 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.

Use of calcitonin in osteoarthritis

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 an established 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.”

See also

• Procalcitonin
• Miacalcin

References

ISBN links support NWE through referral fees

• Wood, D., and T. G. Odle. 2006. In J. L. Longe, The Gale Encyclopedia of Cancer. Detroit, MI: Gale. ISBN 1414403623.

J. Biochem, 1976, Vol. 79, No. 2 353-359

© 1976 Japanese Biochemical Society research-article Amino Acid Sequence of Eel Calcitonin Toshiharu NODA1 and Kozo NARITA

• Ogle, T. E., and A. Costoff. 1999. Endocrinology: Anatomy, structure, and synthesis of calcitonin (CT). Section 5, Chapter 6 in T. M. Novak, Essentials of Human Physiology. Gold Standard Multimedia and Medical College of Georgia. Retrieved May 27, 2008.

http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=SM00113

Simple Modular Architecture Research Tool

Further reading

• MacIntyre I, Alevizaki M, Bevis PJ, Zaidi M (1987). Calcitonin and the peptides from the calcitonin gene.. Clin. Orthop. Relat. Res. (217): 45-55.
• Di Angelantonio S, Giniatullin R, Costa V, et al. (2004). Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells.. Br. J. Pharmacol. 139 (6): 1061-73.
• Findlay DM, Sexton PM (2005). Calcitonin.. Growth Factors 22 (4): 217-24.
• Sponholz C, Sakr Y, Reinhart K, Brunkhorst F (2007). Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature.. Critical care (London, England) 10 (5): R145.
• Schneider HG, Lam QT (2007). Procalcitonin for the clinical laboratory: a review.. Pathology 39 (4): 383-90.

Hormones and endocrine glands

Hypothalamus: GnRH - TRH - CRH - GHRH - somatostatin - dopamine | Posterior pituitary: vasopressin - oxytocin | Anterior pituitary: GH - ACTH - TSH - LH - FSH - prolactin - MSH - endorphins - lipotropin Thyroid: T3 and T4 - calcitonin | Parathyroid: PTH | Adrenal medulla: epinephrine - norepinephrine | Adrenal cortex: aldosterone - cortisol - DHEA | Pancreas: glucagon- insulin - somatostatin | Ovary: estradiol - progesterone - inhibin - activin | Testis: testosterone - AMH - inhibin | Pineal gland: melatonin | Kidney: renin - EPO - calcitriol - prostaglandin | Heart atrium: ANP Stomach: gastrin | Duodenum: CCK - GIP - secretin - motilin - VIP | Ileum: enteroglucagon | Liver: IGF-1 Placenta: hCG - HPL - estrogen - progesterone Adipose tissue: leptin, adiponectin Target-derived NGF, BDNF, NT-3

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