The scent of an ion: calcium-sensing and its roles in health and disease.

The recent cloning of G protein-coupled extracellular Ca2+ (Ca2+o)-sensing receptors from bovine (and human) parathyroid and rat kidney (and brain) has clearly shown that Ca2+o can function as a 'first messenger'. The physiological relevance of this receptor in Ca2+o homeostasis in man has been demonstrated by the identification both of 'inactivating' and of 'activating' mutations in this Ca2+o-sensing receptor, which result in hypercalcemic and hypocalcemic phenotypes, respectively. The molecular mechanisms involved in extracellular calcium 'sensing' in the kidney are just beginning to emerge but are already suggesting new and novel mechanisms for linking Ca2+ (and Mg2+) and water excretion. The latter inter-relationship appears to be crucial because maximal water conservation during periods of increased urinary Ca2+ or Mg2+ loss (e.g. due to increased dietary intake of these solutes) would increase urinary divalent cation concentration and enhance the risk of crystal/stone formation. The interactions among Ca2+, NaCl and water handling in the distal nephron and collecting duct may provide mechanisms for integrating and balancing water and divalent mineral loss, minimizing the risk of stone formation (a 'trade-off' of water conservation for Ca2+ or Mg2+ loss). Research over the next few years should greatly expand our understanding of the roles played by this Ca2+o-sensor both in divalent mineral excretion and in water metabolism as well as in other tissues (e.g. in the central nervous system).