The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [12] and subsequently updated [22]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [23]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [3,34], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [9,12,17,32-33]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [14,42]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [4] or decreased extracellular ionic strength [33] while sensitivity is decreased by pathophysiological phosphate concentrations [5]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [16]. This is seen most clearly in patients with loss-of-function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [16] and in Casr null mice [6,17], which exhibit similar increases in PTH secretion and blood calcium levels. Gain-of-function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [16].

The CaS receptor primarily couples to G_q/11, G_12/13 and G_i/o [11,15,18,37], but in some cell types can couple to G_s [25]. The CaS receptor acts as a homodimer [42]. However, the CaS receptor can also form heteromers with Class C GABA_B [7-8] and mGlu1/5 receptors [13], which may introduce further complexity in its signalling capabilities.

Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [19,27]. Further, etelcalcetide is a novel peptide positive allosteric modulator of the receptor, that also displays weak agonist activity [38]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone (PTH (PTH, P01270)) secretion [29]. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion [28].

Where functional pK_B values are provided for allosteric modulators, this refers to ligand affinity determined in an assay that measures a functional readout of receptor activity (i.e. a receptor signalling assay), as opposed to affinity determined in a radioligand binding assay. The functional pK_B may differ depending on the signalling pathway studied. Consult the 'More detailed page' for the assay description, as well as other functional readouts.

* Key recommended reading is highlighted with an asterisk

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* Brown EM. (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab, 27 (3): 333-43. [PMID:23856263]

Cavanaugh A, Huang Y, Breitwieser GE. (2012) Behind the curtain: cellular mechanisms for allosteric modulation of calcium-sensing receptors. Br J Pharmacol, 165 (6): 1670-1677. [PMID:21470201]

* Conigrave AD, Ward DT. (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab, 27 (3): 315-31. [PMID:23856262]

* Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. (2018) The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol, 15 (1): 33-51. [PMID:30443043]

Khan MA, Conigrave AD. (2010) Mechanisms of multimodal sensing by extracellular Ca(2+)-sensing receptors: a domain-based survey of requirements for binding and signalling. Br J Pharmacol, 159 (5): 1039-50. [PMID:20136834]

* Leach K, Hannan FM, Josephs TM, Keller AN, Møller TC, Ward DT, Kallay E, Mason RS, Thakker RV, Riccardi D et al.. (2020) International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function. Pharmacol Rev, 72 (3): 558-604. [PMID:32467152]

Magno AL, Ward BK, Ratajczak T. (2011) The calcium-sensing receptor: a molecular perspective. Endocr Rev, 32 (1): 3-30. [PMID:20729338]

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* Nemeth EF, Van Wagenen BC, Balandrin MF. (2018) Discovery and Development of Calcimimetic and Calcilytic Compounds. Prog Med Chem, 57 (1): 1-86. [PMID:29680147]

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Subcommittee members: Hans Bräuner-Osborne (Chairperson) Professor, DSc, PhD Head of Section for Experimental Pharmacology Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen Universitetsparken 2 2100 Copenhagen Denmark Katie Leach (Chairperson) Monash Institute of Pharmaceutical Science and Dept. of Pharmacology Monash University 381 Royal Parade Parkville VIC 3052 Australia Wenhan Chang School of Medicine UCSF 4150 Clement Street San Francisco CA 94121 USA Arthur Conigrave School of Molecular and Microbial Biosciences University of Sydney Maze Crescent NSW 02121 Australia Fadil Hannan Department of Clinical Biochemistry and Metabolic Medicine UCD Building Royal Liverpool University Hospital Prescott Street Liverpool L7 8XP UK Daniela Riccardi Cardiff School of Biosciences Cardiff University The Sir Martin Evans Building Museum Avenue Cardiff CF10 3AX UK Polina Yarova Cardiff School of Biosciences Cardiff University The Sir Martin Evans Building Museum Avenue Cardiff CF10 3AX UK

Other contributors: Daniel Bikle Endocrinology University of California School of Medicine San Francisco CA 94121-1598 USA Edward M. Brown (Past chairperson) Division of Endocrinology, Diabetes and hypertension Brigham and Women’s Hospital 221 Longwood Ave. EBRC223 Boston MA 02115 USA Dolores Shoback Endocrine Research Unit (111N) San Francisco CA 94121 USA Donald T. Ward, PhD, FHEA Faculty of Biology, Medicine and Health, The University of Manchester A.1025 Michael Smith Building Oxford Road Manchester, M13 9PT UK