TY - JOUR T1 - Agonists and allosteric modulators of the Calcium Sensing Receptor and their therapeutic applications JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.058784 SP - mol.109.058784 AU - Zuzana Saidak AU - Michel Brazier AU - Said Kamel AU - Romuald Mentaverri Y1 - 2009/01/01 UR - http://molpharm.aspetjournals.org/content/early/2009/09/24/mol.109.058784.abstract N2 - The Calcium sensing Receptor (CaR) belongs to the G protein-coupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C terminal and an extracellular N terminal domain. The primary physiological function of the CaR is the maintenance of constant blood Ca2+ levels, due to its ability to sense very small changes in extracellular Ca2+ (Ca2+o) concentrations. Nevertheless, in addition to being expressed in tissues involved in Ca2+o homeostasis, the CaR is also expressed in tissues not involved in mineral homeostasis, suggestive of additional physiological functions. Numerous agonists and modulators of the CaR are now known in addition to Ca2+o, including various divalent and trivalent cations, aromatic L-amino acids, polyamines, and aminoglycoside antibiotics. The signaling of the CaR is also regulated by extracellular pH and ionic strength. The activated CaR couples mainly to the phospholipase Cβ and ERK1/2 signaling pathways, and it decreases intracellular cAMP levels, leading to various physiological effects. The recent identification of synthetic allosteric modulators of the CaR has opened up a new field of research possibilities. Calcimimetics and calcilytics, which increase and decrease agonist signaling via the CaR, respectively, may facilitate the manipulation of the CaR, and thus aid in further investigations of its precise signaling. These allosteric modulators, as well as strontium, have been demonstrated to have therapeutic potential for the treatment of disorders involving the CaR. This review discusses the various agonists and modulators of the CaR, differences in their binding and signaling, and their roles as therapeutics in various diseases.The American Society for Pharmacology and Experimental Therapeutics ER -