Very small changes in ionized calcium induce rapid changes in PTH secretion in order to keep the extracellular calcium concentration constant or within its narrow normal range. For nearly 20 years, clinical investigations and in vitro studies have suggested that sensing extracellular calcium is altered in various disorders of plasma calcium regulation. Set point abnormalities in the regulation of PTH secretion by extracellular calcium have been established in various diseases, such as hyperparathyroidism and familial benign hypocalciuric hypercalcaemia (FBHH). The calcium sensing receptor (CaSR) was recently cloned from bovine parathyroid tissue. This receptor enables the parathyroid cells to detect and respond to these minute changes. It is a 120-kD polypeptide with seven transmembrane domains characteristic of the superfamily of G protein-coupled cell surface receptors and with a very large extracellular N-terminal domain that resembles metabotropic glutamate receptors. Functional studies using chimeras of metabotropic glutamate and calcium receptor suggest that the extracellular domain of the CaSR is the major binding site for extracellular calcium. An activated CaSR produces an increase in cytosolic free calcium concentration via activation of the phospholipase C/inositol triphosphate signal transduction pathway. The CaSR gene is located on chromosome 3q.