The many roles of the calcium-sensing receptor in health and disease.

The physiological relevance of calcium in many vital processes requires that its concentration in extracellular fluids be kept within a narrow range. The near-constancy of this parameter emphasizes the remarkable sensitivity of cells sensing changes in extracellular calcium concentration to minimal fluctuations (< 2%) and the level of sophistication of the homeostatic system (1). The identification of a cell surface, Ca2+ (polyvalent cation)-sensing receptor (CaR), has shed considerable light on the molecular aspects of hypercalcemia on cell function (2). Activation of the receptor by calcium triggers an intracellular cascade of second messengers producing a variety of biological effects, many of which have yet to be understood. This suggests, for the first time, that Ca2+ can exert its effects in a hormone-like fashion without crossing the plasma membrane. The demonstration that inherited genetic disorders of Ca2+ homeostasis are associated with mutations that reduce or enhance responsiveness of the receptor to extracellular Ca2+ concentration clearly proposes CaR as the main regulator of divalent mineral ion excretion (3). This hypothesis is confirmed by the assessment of the presence of the receptor in all regions involved in Ca2+ homeostasis (e.g., parathyroid glands, kidney, calcitonin-secreting C cells, bone-derived cell lines, and intestine) (1,4-8). Recently, the receptor has also been found in regions not normally involved in mineral ion metabolism, such as the brain, eye, stomach, and pancreas (9-13). This clearly indicates a much broader relevance of CaR in the maintenance of local ionic homeostasis and, possibly, in the involvement in vital processes such as the regulation of cell fate.