Therapeutic Opportunities of Targeting Allosteric Binding Sites on the Calcium-Sensing Receptor

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The CaSR is a class C G protein-coupled receptor (GPCR) that acts as a multimodal chemosensor to maintain diverse homeostatic functions. The CaSR is a clinical therapeutic target in hyperparathyroidism and has emerged as a putative target in several other diseases. These include hyper- and hypocalcaemia caused either by mutations in the CASR gene or in genes that regulate CaSR signaling and expression, and more recently in asthma. The development of CaSR-targeting drugs is complicated by the fact that the CaSR possesses many different binding sites for endogenous and exogenous agonists and allosteric modulators. Binding sites for endogenous and exogenous ligands are located throughout the large CaSR protein and are interconnected in ways that we do not yet fully understand. This review summarizes our current understanding of CaSR physiology, signaling, and structure and how the many different binding sites of the CaSR may be targeted to treat disease.

Original languageEnglish
Pages (from-to)666–679
Number of pages14
JournalACS Pharmacology & Translational Science
Issue number2
Publication statusPublished - 9 Apr 2021


  • ADH
  • allosteric modulator
  • asthma
  • CaSR
  • CASR gene
  • FHH
  • hyperparathyroidism
  • osteoporosis

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