Human Biochemistry, Volume 2 - Murray R. 1993
Biochemistry of Intra- and Intercellular Communication
Hormones Regulating Calcium Metabolism
Hormones Involved in Calcium Homeostasis - Calcitonin (CT)
Origin and Structure
Calcitonin (CT) is a peptide consisting of 32 amino acid residues (Fig. 47.6). In humans, it is secreted by the parafollicular C-Cells of The Thyroid Gland (less commonly by the parathyroid gland or Thymus), while in other species it is produced by homologous cells located in the ultimobranchial glands. These cells originate from the neural crest and are biologically related to the cells of many other Endocrine glands.
The biological activity of CT requires the integrity of the entire molecule, including the 7-membered N-terminal loop formed by a disulfide bond. There is extensive interspecies Variability in the Amino Acid Sequence of calcitonins (human and porcine CT share only 14 out of 32 amino acid residues). Despite these differences, they exhibit cross-species biological activity (i.e., CT from one animal species remains biologically active when administered to other species). The most potent natural CT isolated to date is derived from salmon.
Regulation of Secretion
The secretion rates of CT and PTH are inversely related (Fig. 43.3) and regulated by the concentration of ionized calcium (and likely magnesium) in the ECF. CT secretion increases in proportion to Ca2+ concentrations ranging from 9.5 to 15 mg%. Glucagon and pentagastrin are potent stimulators of CT release, with the latter used as a provocative agent in diagnostic testing for medullary thyroid carcinoma (malignant transformation of parafollicular C-cells).
The history of CT research is unique. Within seven years (1962–1968), CT was discovered, isolated, sequenced, and synthesized, yet its physiological role in humans remains somewhat elusive. Thyroidectomy in animals does not induce hypercalcemia, and administration of CT to healthy subjects fails to cause a notable drop in Blood calcium levels.
In assay systems, the primary target of CT is bone, where the hormone inhibits matrix resorption, thereby reducing the release of calcium and phosphate. This effect of CT is independent of PTH. CT elevates cAMP levels in bone, presumably by acting on cells that are not targeted by PTH.
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Fig. 47.6. Structure of human calcitonin.
CT also exerts a marked effect on phosphate METABOLISM. It promotes the influx of phosphate into bone cells and periosteal fluid while suppressing the efflux of calcium from bones into Blood Plasma. This phosphate uptake may be accompanied by calcium influx, given that the hypocalcemic effect of CT is phosphate-dependent. This action of CT, combined with its ability to inhibit osteoclast-mediated bone resorption, helps explain the therapeutic efficacy of this hormone in managing Cancer-associated hypercalcemia.
Clinical manifestations of CT deficiency have not been clearly established. CT excess occurs in medullary thyroid carcinoma (MTC), a condition that may be either sporadic or familial. Although CT levels in MTC frequently exceed normal values by a thousandfold, this is rarely accompanied by hypocalcemia. While the Biological Significance of such elevated CT levels remains unclear, the finding is of great diagnostic value. Plasma CT measurements, often performed following stimulation with secretagogues such as calcium or pentagastrin, allow for the early Diagnosis of this serious disease while it is still amenable to Treatment.
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