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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, <i>γ</i>-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca<sup>2+</sup> <sub>o</sub>) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca<sup>2+</sup> <sub>o</sub> homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca<sup>2+</sup> <sub>o</sub> homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca<sup>2+</sup> <sub>o</sub>, an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G<sub>q/11</sub>, G<sub>i/o</sub>, potentially G<sub>12/13</sub>, and even G<sub>s</sub> in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. SIGNIFICANCE STATEMENT: The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

Original publication

DOI

10.1124/pr.119.018531

Type

Journal article

Journal

Pharmacological reviews

Publication Date

07/2020

Volume

72

Pages

558 - 604

Addresses

Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University, Parkville, Australia (K.L., T.M.J., A.N.K.); Nuffield Department of Women's & Reproductive Health (F.M.H.) and Academic Endocrine Unit, Radcliffe Department of Clinical Medicine (F.M.H., R.V.T.), University of Oxford, Oxford, United Kingdom; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (T.C.M., H.B.-O.); Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (D.T.W.); Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (E.K.); Physiology, School of Medical Sciences and Bosch Institute (R.S.M.) and School of Life & Environmental Sciences, Charles Perkins Centre (A.D.C.), University of Sydney, Sydney, Australia; and School of Biosciences, Cardiff University, Cardiff, United Kingdom (D.R.) katie.leach@monash.edu.

Keywords

Animals, Humans, GTP-Binding Proteins, Receptors, Calcium-Sensing, Signal Transduction, Binding Sites, Models, Molecular, Small Molecule Libraries