Calcium-sensing Receptor/CaSR Protein, Human (HEK293, His)

The Calcium-sensing Receptor/CaSR Protein, a G-protein-coupled receptor, plays a pivotal role in detecting changes in extracellular calcium concentration, crucial for maintaining calcium homeostasis. This receptor senses fluctuations in circulating calcium levels and modulates the production of parathyroid hormone (PTH) in parathyroid glands. Its activity is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. The receptor's activation involves a co-agonist mechanism, where aromatic amino acids such as Trp or Phe, in concert with divalent cations like calcium or magnesium, achieve full activation. In the resting state, the receptor adopts an open conformation, with anion binding promoting the inactive configuration. Upon aromatic amino acid binding, the extracellular venus flytrap module groove closes, inducing a novel homodimer interface between subunits. Calcium ions further stabilize the active state by enhancing homodimer interactions between membrane-proximal domains. Notably, the receptor can be activated by AMG 416, a D-amino acid-containing peptide agonist under evaluation for treating secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis, with AMG 416 acting through the formation of a disulfide bond with Cys-482.