Calcium ions as extracellular, first messengers.

Ca2+ concentration in the extracellular fluids ([Ca2+]o) is essential for a number of vital processes from bone formation to blood clotting. For this reason, it is necessary that [Ca2+]o must be strictly controlled. Mammalian species have developed a complex homeostatic system that includes parathyroid glands, kidney and bone. The extracellular Ca(2+)-sensing receptor (CaR) is an essential component of this system, regulating parathyroid hormone secretion, calcium excretion by the kidney and bone remodeling. Initially identified from bovine parathyroid glands (1), within the five years following its identification CaR presence has rapidly been extended to organs where the link with mineral ion metabolism has not been elucidated (i.e., brain, stomach, eye, skin, and many other epithelial cells) (see 2 for review). This review will address the discovery of a novel class of ionsensing receptors, receptor-effector coupling, and the roles of the CaR inside and outside the Ca2+o homeostatic system.