Disease Related Mutations Adjacent to Predicted Multiple Ca2+ Binding Sites of Ca2+-Sensing Receptor Altering Intracellular Ca2+ Oscillations via Extracellular Calcium and Amino Acid Signaling

摘要: Calcium sensing receptor (CaSR), along other members of the family C G protein-coupled receptors (GPCRs), play very important roles in responding to changes extracellular calcium concentrations and circulating levels amino acids integrating these signals into alterations intracellular signaling pathways. We have reported several potential calcium-binding sites located within CaSR's domain using our developed computational algorithms. In present study, we first report differential effects disease-related mutations at predicted binding on inhibition activation responses single cell imaging. Interestingly, mutating different residues two locations near hinge region ECD could lead either significantly lose function or gain (switch mutations). Amino acid results rescue effect altering responses, especially oscillations. further analyzed mutation correlation motion, cooperativity, synergistic use methods. These provide implications for understanding how CaSR integrates information about completely classes agonists--an inorganic divalent cation, another hand, a nutrient-- senses agonists healthy diseased states.