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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.<\/jats:p>","DOI":"10.1021\/acsptsci.1c00046","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T09:58:45Z","timestamp":1615197525000},"page":"666-679","source":"Crossref","is-referenced-by-count":26,"title":["Therapeutic Opportunities of Targeting Allosteric\nBinding Sites on the Calcium-Sensing Receptor"],"prefix":"10.1021","volume":"4","author":[{"given":"Jiayin","family":"Diao","sequence":"first","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"DeBono","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]},{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-3683","authenticated-orcid":true,"given":"Tracy M.","family":"Josephs","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane E.","family":"Bourke","sequence":"additional","affiliation":[{"name":"Biomedicine Discovery Institute, Monash University , , 9 Ancora Imparo Way , , ,","place":["Clayton, Victoria, Australia, 3800"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5434-0180","authenticated-orcid":true,"given":"Ben","family":"Capuano","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3833-2137","authenticated-orcid":true,"given":"Karen J.","family":"Gregory","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]},{"name":"Biomedicine Discovery Institute, Monash University , , 9 Ancora Imparo Way , , ,","place":["Clayton, Victoria, Australia, 3800"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-1803","authenticated-orcid":true,"given":"Katie","family":"Leach","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]},{"name":"Biomedicine Discovery Institute, Monash University , , 9 Ancora Imparo Way , , ,","place":["Clayton, Victoria, Australia, 3800"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"2026081904090923300_cit1","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1124\/pr.119.018531","article-title":"International\nUnion of Basic and Clinical Pharmacology. 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Exp. Ther."},{"key":"2026081904090923300_cit31","doi-asserted-by":"publisher","first-page":"5","DOI":"10.7554\/eLife.13662","article-title":"Structural mechanism\nof ligand activation in human calcium-sensing receptor","author":"Geng","year":"2016","journal-title":"eLife"},{"key":"2026081904090923300_cit32","doi-asserted-by":"publisher","first-page":"14147","DOI":"10.1074\/jbc.M307422200","article-title":"Modulation\nof interprotomer relationships is important for activation of dimeric\ncalcium-sensing receptor","volume":"279","author":"Jiang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2026081904090923300_cit33","doi-asserted-by":"publisher","first-page":"e1600241","DOI":"10.1126\/sciadv.1600241","article-title":"Structural\nbasis for regulation of human calcium-sensing receptor by magnesium\nions and an unexpected tryptophan derivative co-agonist","volume":"2","author":"Zhang","year":"2016","journal-title":"Sci. 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