Extracellular Calcium Sensing and Extracellular Calcium Signaling

The cloning of a G protein-coupled extracellular Ca2+(Cao2+)-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Cao2+on tissues that maintain systemic Cao2+homeostasis, especially parathyroid chief cells and several cells in the kidney. The availability of the cloned CaR enabled the development of DNA and antibody probes for identifying the CaR's mRNA and protein, respectively, within these and other tissues. It also permitted the identification of human diseases resulting from inactivating or activating mutations of the CaR gene and the subsequent generation of mice with targeted disruption of the CaR gene. The characteristic alterations in parathyroid and renal function in these patients and in the mice with “knockout” of the CaR gene have provided valuable information on the CaR's physiological roles in these tissues participating in mineral ion homeostasis. Nevertheless, relatively little is known about how the CaR regulates other tissues involved in systemic Cao2+homeostasis, particularly bone and intestine. Moreover, there is evidence that additional Cao2+sensors may exist in bone cells that mediate some or even all of the known effects of Cao2+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 Cao2+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 control of gene expression, programmed cell death (apoptosis), and cellular proliferation. In some cases, the CaR on these “nonhomeostatic” cells responds to local changes in Cao2+taking place within compartments of the extracellular fluid (ECF) that communicate with the outside environment (e.g., the gastrointestinal tract). In others, localized changes in Cao2+within the ECF can originate from several mechanisms, including fluxes of calcium 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/sensors for Cao2+and probably for other extracellular ions represent versatile regulators of numerous cellular functions and may serve as important therapeutic targets.