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 calcium concentration(Ca-o(2+)) with exquisite sensitivity, but the mechanisms through which it senses Ca-o(2+) have remained obscure. Recently, we isolated a cDNA encoding a Ca-o(2+)-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The expressed receptor stimulates phospholipase C and has a pharmacological profile almost identical to that of the native receptor. Furthermore, its deduced amino acid sequence confirms that it belongs to the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid and other tissues sensing Ca-o(2+) (e.g., kidney and thyroidal C-cells) as well as those not known to be involved in Ca2+ homeostasis (viz., in the brain). We have also shown that mutations in the receptor cause three inherited disorders of calcium metabolism: Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) result from inactivating mutations, when present in the heterozygous and homozygous states, respectively, whereas an autosomal dominant form of hypocalcemia is due to an activating mutation. Thus this Ca-o(2+)-sensing receptor permits Ca-o(2+) to act as an extracellular, first messenger in addition to its better known role as an intracellular second messenger.