THE CLONING OF EXTRACELLULAR CA2-SENSING RECEPTORS FROM PARATHYROID AND KIDNEY - MOLECULAR MECHANISMS OF EXTRACELLULAR CA2+-SENSING()

The parathyroid cell detects changes in the extracellular ionized calc ium concentration(Ca-o(2+)) with exquisite sensitivity, but the mechan isms through which it senses Ca-o(2+) have remained obscure. Recently, we isolated a cDNA encoding a Ca-o(2+)-sensing receptor from bovine p arathyroid using expression cloning in Xenopus laevis oocytes. The exp ressed receptor stimulates phospholipase C and has a pharmacological p rofile almost identical to that of the native receptor. Furthermore, i ts deduced amino acid sequence confirms that it belongs to the superfa mily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid and other tissues sensing Ca-o(2+) (e.g., kidney and th yroidal C-cells) as well as those not known to be involved in Ca2+ hom eostasis (viz., in the brain). We have also shown that mutations in th e receptor cause three inherited disorders of calcium metabolism: Fami lial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparath yroidism (NSHPT) result from inactivating mutations, when present in t he heterozygous and homozygous states, respectively, whereas an autoso mal dominant form of hypocalcemia is due to an activating mutation. Th us this Ca-o(2+)-sensing receptor permits Ca-o(2+) to act as an extrac ellular, first messenger in addition to its better known role as an in tracellular second messenger.