The calcium-sensing receptor (CaSR) is a class C G-protein-coupled receptor encoded by a single copy gene. CaSR plays a major role in the maintenance of a physiological serum ionized Ca²⁺ concentration by regulating the circulating levels of parathyroid hormone¹.

The N-terminus of the receptor is comprised of a signal peptide of 19 amino acids. This terminus directs the nascent CaSR polypeptide into the lumen of the endoplasmic reticulum (ER) and is then cleaved. The extracellular domain (ECD) of the mature protein has approximately 600 amino acids, comprised of a bi-lobed Venus-flytrap-like domain (VFT) connected by a cysteine-rich region and a short peptide linker to the seven transmembrane domain (TMD) with an intracellular C-terminal tail of 216 amino acids. CaSR functions as a homodimer with both covalent and noncovalent interactions between the VFT domains of each monomer. Ca²⁺ binds in the cleft between the two lobes of each VFT causing the lobes to close on one another and the VFT to rotate with transfer of a conformational change to the cysteine-rich region.

In the parathyroid gland, up-regulation of CaSR by 1,25-dihydroxyvitamin D [1,25(OH)2D] makes the gland more responsive to extracellular Ca²⁺ and parathyroid hormone (PTH) secretion is reduced. While somatic mutations in CASR are rare, parathyroid glands from patients with primary or severe uremic secondary hyperparathyroidism have reduced CaSR expression².