Calcitonin

CALCA
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 2JXZ,%%s1LS7
Identifiers
Aliases	CALCA , CT, CGRP-I, CGRP-alpha, KC, PCT, calcitonin related polypeptide alpha, CGRP, CGRP1, CALC1
External IDs	OMIM: 114130 HomoloGene: 88401 GeneCards: CALCA
Gene location (Human) Chr. Chromosome 11 (human) [1] Band 11p15.2 Start 14,966,668 bp [1] End 14,972,351 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in spinal ganglia trigeminal ganglion kidney quadriceps femoris muscle vastus lateralis muscle cerebellar vermis islet of Langerhans tibialis anterior muscle right lobe of liver left lobe of thyroid gland n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hormone activity calcitonin receptor binding protein binding identical protein binding signaling receptor binding protein-containing complex binding Cellular component cytoplasm intracellular anatomical structure extracellular region axon terminal bouton neuronal cell body neuron projection nucleus extracellular space Biological 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 negative regulation of smooth muscle contraction regulation of heart contraction monocyte chemotaxis negative regulation of blood pressure positive regulation of cytosolic calcium ion concentration cellular response to tumor necrosis factor human ageing vasodilation cellular calcium ion homeostasis response to heat negative regulation of nervous 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 regulation of signaling receptor activity G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway regulation of cytosolic calcium ion concentration leukocyte cell-cell adhesion G protein-coupled receptor internalization positive regulation of interleukin-1 alpha production response to yeast 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 nervous 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 amylin receptor signaling pathway calcitonin gene-related peptide receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 796 n/a Ensembl ENSG00000110680 n/a UniProt P06881 n/a RefSeq (mRNA) NM_001033952 NM_001033953 NM_001741 NM_001378949 NM_001378950 n/a RefSeq (protein) NP_001029125.1 n/a Location (UCSC) Chr 11: 14.97 – 14.97 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates ^[3] in the ultimopharyngeal body. ^[4] It acts to reduce blood calcium (Ca²⁺), opposing the effects of parathyroid hormone (PTH). ^[5]

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. ^[6] It belongs to the calcitonin-like protein family.

Historically calcitonin has also been called thyrocalcitonin. ^[7]

Biosynthesis and regulation

Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene ( CALCA ). It is functionally an antagonist with PTH and Vitamin D3. 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 Calcium [Ca²⁺] ^[8]
• gastrin and pentagastrin. ^[9]

Function

Main article: Calcium metabolism

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

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

• Major effect: Inhibits osteoclast activity in bones, which break down the bone ^[10]
• Minor effect: Inhibits renal tubular cell reabsorption of Ca²⁺ and phosphate, allowing them to be excreted in the urine ^{[11] [12]}

High concentrations of calcitonin may be able to increase urinary excretion of calcium and phosphate via the renal tubules. ^[13] leading to marked hypocalcemia. 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. ^[14]

In its skeleton-preserving actions, calcitonin protects against calcium loss from the 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. ^{[15] [16] [17]}

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 increased osteoblastic activity (as an indirect effect). ^[14]

Receptor

Structure of human calcitonin recptor-G_s complex. The transmembrane calcitonin receptor (blue) is bound to human calcitonin (red) and the G_s complex (yellow). PDB: 7TYO ​

The calcitonin receptor is a G protein-coupled receptor localized to osteoclasts ^[18] as well kidney and brain cells. It is coupled to a G_sα subunit, thus stimulating cAMP production by adenylate cyclase in target cells. It may also affect the ovaries in women and the testes in men.^{[ citation needed ]}

Discovery

Calcitonin was first purified in 1962 by Douglas Harold Copp and B. Cheney at the University of British Columbia, Canada. ^[19] It was initially thought to be secreted by the parathyroid gland but was shown by Iain Macintyre and his team at the Royal Postgraduate Medical School, London, to be secreted by parafollicular cells of the thyroid gland. ^[20] Dr. Copp named the discovered hormone calcitonin because of its role in 'maintaining normal calcium tone'. ^[19]

Clinical significance

Calcitonin assay is used in identifying patients with nodular thyroid diseases. It is helpful in making an early diagnosis of medullary carcinoma of thyroid. A malignancy of the parafollicular cells, i.e. Medullary thyroid cancer (MTC), typically produces an elevated serum calcitonin level. Prognosis of MTC depends on early detection and treatment.

Calcitonin also has significantly impacted molecular biology, as the gene encoding calcitonin was the first gene discovered in mammalian cells to be alternatively spliced, now known to be a ubiquitous mechanism in eukaryotes. ^{[21] [22]}

Pharmacology

Calcitonin has clinically been used for metabolic bone disorders for more than 50 years. ^[23] Salmon calcitonin is used for the treatment of:

• Postmenopausal osteoporosis ^[24]
• Hypercalcaemia ^[25]
• Bone metastases ^[26]
• Paget's disease ^[27]
• Phantom limb pain ^[28]

It has been investigated as a possible non-operative treatment for spinal stenosis. ^[29]

The following information is from the UK Electronic Medicines Compendium ^[30]

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 kidney 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. ^[31] 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. ^[30]

Uses of calcitonin

Treatments

Calcitonin affecting the spine.

Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis. ^[32] 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. ^[33]

Subcutaneous injections of calcitonin in patients with mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder. ^[34] 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: ^[35]

• 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

A Cochrane systematic review assessed the diagnostic accuracy of basal and stimulated calcitonin for Medullary Thyroid cancer. ^[36] Although both basal and combined basal and stimulated calcitonin testing presented high accuracy (sensitivity: between 82% and 100%; specificity: between 97.2% and 100%), these results had a high risk of bias due to design flaws of included studies. ^[36] Overall, the value of routine testing of calcitonin for diagnosis and prognosis of Medullary Thyroid Cancer remains uncertain and questionable. ^[36]

Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, nonthyroidal oat cell carcinoma, nonthyroidal carcinoma and other nonthyroidal malignancies, acute kidney injury and chronic kidney failure, hypercalcemia, hypergastrinemia, and other gastrointestinal disorders, and pulmonary disease. ^[37]

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. ^[38] 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. ^[39]

The following are the amino acid sequences of salmon and human calcitonin:^{[ citation needed ] [40]}

• 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.

Research

In addition to the injectable and nasal spray dosage forms of the salmon calcitonin, noninvasive oral formulations of the peptide are currently under clinical development. The short-half-life of this peptide in serum triggered several attempts to enhance plasma concentrations. The peptide is complexed with a macromolecule that acts as an absorption enhancer through the transcellular pathway and, additionally, protects the peptide from the harsh pH and enzymatic conditions of the GI tract. This complexation is weak, noncovalent and reversible and the drug remains chemically unmodified. After passage through the intestine, the delivery agent dissociates from the peptide. One of the extensively studied oral formulations is the disodium salts of 5-CNAC oral calcitonin. This novel oral platform in a number of clinical trials at different phases has demonstrated promising enhanced pharmacokinetic profile, high bioavailability, well-established safety and comparable efficacy to that of nasal calcitonin especially for treatment of postmenopausal bone loss. ^[23]

See also

• Procalcitonin

References

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17. Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS (September 2006). "Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation". Endocrinology. 147 (9): 4010–4021. doi: 10.1210/en.2005-1616 . PMID   16675524.
18. Nicholson GC, Moseley JM, Sexton PM, Mendelsohn FA, Martin TJ (August 1986). "Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization". J. Clin. Invest. 78 (2): 355–360. doi:10.1172/JCI112584. PMC   423551 . PMID   3016026.
19. Copp DH, Cheney B (January 1962). "Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood". Nature. 193 (4813): 381–2. Bibcode:1962Natur.193..381C. doi:10.1038/193381a0. PMID   13881213. S2CID   4292938.
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Further reading

• MacIntyre I, Alevizaki M, Bevis PJ, Zaidi M (April 1987). "Calcitonin and the peptides from the calcitonin gene". Clinical Orthopaedics and Related Research. 217 (217): 45–55. doi:10.1097/00003086-198704000-00007. PMID   3549095.
• Di Angelantonio S, Giniatullin R, Costa V, Sokolova E, Nistri A (July 2003). "Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells". British Journal of Pharmacology. 139 (6): 1061–1073. doi:10.1038/sj.bjp.0705337. PMC   1573932 . PMID   12871824.
• Findlay DM, Sexton PM (December 2004). "Calcitonin". Growth Factors. 22 (4): 217–224. doi:10.1080/08977190410001728033. PMID   15621724. S2CID   218910711.
• 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. 10 (5): R145. doi: 10.1186/cc5067 . PMC   1751067 . PMID   17038199.
• Schneider HG, Lam QT (August 2007). "Procalcitonin for the clinical laboratory: a review". Pathology. 39 (4): 383–390. doi:10.1080/00313020701444564. PMID   17676478. S2CID   28018130.
• Grani G, Nesca A, Del Sordo M, Calvanese A, Carbotta G, Bianchini M, Fumarola A (June 2012). "Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis". Endocrine-Related Cancer. Bioscientifica. 19 (3): 345–349. doi: 10.1530/ERC-12-0013 . PMID   22399011.

External links

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