Calcitonin Gene-Related Peptide and Its Receptors: Molecular Genetics, Physiology, Pathophysiology, and Therapeutic Potentials

I. IntroductionTHE calcitonin (CT) and calcitonin gene-related peptide (CGRP) are derived from the CT/CGRP gene, which is localized in chromosome 11. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. This alternative tissue-specific processing of primary mRNA from the α-CT/CGRP gene in rats generates two distinct peptides, CT and CGRP (1, 2). CGRP is a 37-amino acid neuropeptide expressed predominantly in the nervous system and CT is expressed mainly in the thyroid gland. CGRP receptors, widely distributed in the body, are the most potent endogenous vasodilatory peptides that have been discovered. Derived from the C cells of the thyroid gland, CT is the most potent peptide inhibitor of osteoclast-mediated bone resorption and is involved primarily in protecting the skeleton during periods of "calcium stress" such as growth, pregnancy, and lactation (3).In 1961, Copp and colleagues (4) postulated the existence of the calcium-lowering peptide CT. Its sequence and structure were determined by Neher et al. in 1968 (5). Similar to CGRP and amylin, CT is a single-chain peptide hormone consisting of 32 amino acids. In humans, CT is secreted by the parafollicular cells (C cells) of the thyroid (6, 7), which are of neural crest origin (8). In addition, a minority of CT-producing cells are also in the bronchial Kulchitsky (K) cells in the lungs (9). These K cells have been shown to be the origin of bronchial carcinoid and small cell carcinoma of the lung, both of which secrete CT (10, 11). Therefore, even after total thyroidectomy, the complete absence of CT from the circulation is unlikely, and minute amounts of CT in the circulation may be sufficient to counteract the bone-resorbing effects of other hormones such as PTH (12).