The ability of the parathyroid cell to sense minute fluctuations in the extracellular ionized calcium concentration (Ca2+ o) is essential for maintaining mineral ion homeostasis. However, the mechanism(s) through which the parathyroid cell and other cells recognize and respond to changes in Ca2+ o has remained unclear. We recently isolated a cDNA encoding a Ca2+ o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The receptor shows pharmacologic properties that are almost identical to those of the receptor on the parathyroid cell and, like the latter, stimulates phospholipase C in a G-protein-dependent manner. The amino acid sequence of the cloned receptor deduced from this cDNA predicts a protein with a molecular mass of 121 kd, which has three principal structural domains. The first is a 613 amino acid, putatively extracellular amino terminus which has several regions rich in acidic amino acids that may potentially be involved in binding Ca2+ and other polycationic agonists. The second comprises seven membrane-spanning segments that are characteristic of the superfamily of G-protein-coupled receptors, and the third is a 222 amino acid cytoplasmic tail. Transcripts for this Ca2+ o-sensing receptor are present in the parathyroid as well as in the kidney, thyroid, and brain. We next investigated the hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, as possible examples of inherited abnormalities in this Ca2+ o-sensing receptor, since both disorders show abnormal Ca2+ o-sensing and/or handling in the kidney and parathyroid.(ABSTRACT TRUNCATED AT 250 WORDS)