Extracellular calcium sensing and extracellular calcium signaling

The cloning of a G protein-coupled extracellular Ca2+ (Ca-o(2+))-sensing re ceptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca-o(2+) on tissues that maintain systemic Ca-o(2+) h omeostasis, especially parathyroid chief cells and several cells in the kid ney. The availability of the cloned CaR enabled the development of DNA and antibody probes for identifying the CaR's mRNA and protein, respectively, w ithin these and other tissues. It also permitted the identification of huma n diseases resulting from inactivating or activating mutations of the CaR g ene and the subsequent generation of mice with targeted disruption of the C aR gene. The characteristic alterations in parathyroid and renal function i n these patients and in the mice with "knockout" of the CaR gene have provi ded valuable information on the CaR's physiological roles in these tissues participating in mineral ion homeostasis. Nevertheless, relatively little i s known about how the CaR regulates other tissues involved in systemic Ca-o (2+) homeostasis, particularly bone and intestine. Moreover, there is evide nce that additional Ca-o(2+) sensors may exist in bone cells that mediate s ome or even all of the known effects of Ca-o(2+) on these cells. Even more remains to be learned about the CaR's function in the rapidly growing list of cells that express it but are uninvolved in systemic Ca-o(2+) metabolism . Available data suggest that the receptor serves numerous roles outside of systemic mineral ion homeostasis, ranging from the regulation of hormonal secretion and the activities of various ion channels to the longer term con trol of gene expression, programmed cell death (apoptosis), and cellular pr oliferation. In some cases, the CaR on these "nonhomeostatic" cells respond s to local changes in Ca-o(2+) taking place within compartments of the extr acellular fluid (ECF) that communicate with the outside environment (e.g., the gastrointestinal tract). Ln others, localized changes in Ca-o(2+) withi n the ECF can originate from several mechanisms, including fluxes of calciu m ions into or out of cellular or extracellular stores or across epithelium that absorb or secrete Ca2+. In any event, the CaR and other receptors/sen sors for Ca-o(2+) and probably for other extracellular ions represent versa tile regulators of numerous cellular functions and may serve as important t herapeutic targets.