Illuminating the allosteric modulation of the calcium-sensing receptor
Hongkang Liu, Ping Yi, Wenjing Zhao, Yuling Wu, Francine Acher, Jean‐Philippe Pin, Jianfeng Liu, Philippe Rondard
Abstract
Significance G protein-coupled receptors regulate several physiological processes, many of which sense nutrients. The mode of action of these nutrients remains elusive, as it is difficult to control nutrient concentrations around living cells. The calcium-sensing receptor is regulated by multiple factors, including ions and amino acids, to control calcium homeostasis; and genetic mutations are responsible for human diseases. Here, we investigated this receptor in a perfect control of ambient nutrients. Based on the identification of calcium ion activation sites, we propose a molecular basis for how calcium and amino acids cooperate to control receptor activation. This leads to a model for the mechanism of activation of this receptor and its modulation by multiple ligands and genetic mutations.