Cooperative multi-modal sensing and therapeutic implications of the extracellular Ca(2+) sensing receptor

The extracellular Ca(2+)-sensing receptor (CaR) is an unusual member of the diverse superfamily of seven-transmembrane domain G-protein-coupled receptors. Originally identified as the receptor providing the calciostat for extracellular ionized Ca(2+) ¿[Ca(2+)](o)¿, the CaR corrects small changes in [Ca(2+)](o) by regulating the secretion of the hormone that controls Ca(2+) fluxes between the blood and Ca(2+) stores in bone, and between blood and the urine. Now, research is beginning to reveal the structure and function of its unusually large N-terminal head. In addition to its role as a divalent and polyvalent cation sensor, recent studies indicate that the receptor also responds sensitively to changes in ionic strength and pH. Furthermore, new work indicates that the CaR is subject to allosteric activation by L-amino acids.