Illuminating the allosteric modulation of the calcium-sensing receptor

Proc Natl Acad Sci U S A. 2020 Sep 1;117(35):21711-21722. doi: 10.1073/pnas.1922231117. Epub 2020 Aug 19.


Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cell-free Förster resonance energy transfer (FRET)-based conformational CaSR biosensor to clarify the main conformational changes associated with activation. By allowing a perfect control of ambient nutrients, this assay revealed that Ca2+ alone fully stabilizes the active conformation, while amino acids behave as pure positive allosteric modulators. Based on the identification of Ca2+ activation sites, we propose a molecular basis for how these different ligands cooperate to control CaSR activation. Our results provide important information on CaSR function and improve our understanding of the effects of genetic mutations responsible for human diseases. They also provide insights into how a receptor can integrate signals from various nutrients to better adapt to the cell response.

Keywords: G protein-coupled receptor; allosteric modulator; amino acids; calcium; nutrient sensing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / physiology
  • Binding Sites / genetics
  • Calcium / metabolism*
  • Calcium / physiology
  • Fluorescence Resonance Energy Transfer / methods
  • Humans
  • Ligands
  • Molecular Conformation
  • Receptors, Calcium-Sensing / metabolism*
  • Receptors, Calcium-Sensing / physiology
  • Receptors, Calcium-Sensing / ultrastructure*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction


  • Ligands
  • Receptors, Calcium-Sensing
  • Receptors, G-Protein-Coupled
  • Calcium