Calcium-sensing receptor

Overview

The calcium-sensing receptor (CaS) 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... [read more] analogues, ionic strength and extracellular pH (reviewed in [1]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [2,3], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [4,5,6,7,8]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [9,10]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [11] or decreased extracellular ionic strength [8]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

References

1. Leach K, Sexton PM, Christopoulos A, et al. Engendering biased signalling from the calcium-sensing receptor for the pharmacotherapy of diverse disorders. Br J Pharmacol 2014;171:1142-55.
2. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993;366:575-80.
3. Quinn SJ, Ye CP, Diaz R, et al. The Ca2+-sensing receptor: a target for polyamines. Am J Physiol 1997;273:C1315-23.
4. Conigrave AD, Quinn SJ, Brown EM. L-amino acid sensing by the extracellular Ca2+-sensing receptor. Proc Natl Acad Sci USA 2000;97:4814-9.
5. Foord SM, Bonner TI, Neubig RR, et al. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev 2005;57:279-88.
6. Ho C, Conner DA, Pollak MR, et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 1995;11:389-94.
7. Quinn SJ, Bai M, Brown EM. pH Sensing by the calcium-sensing receptor. J Biol Chem 2004;279:37241-9.
8. Quinn SJ, Kifor O, Trivedi S, et al. Sodium and ionic strength sensing by the calcium receptor. J Biol Chem 1998;273:19579-86.
9. Zhang C, Miller CL, Gorkhali R, et al. Molecular Basis of the Extracellular Ligands Mediated Signaling by the Calcium Sensing Receptor. Front Physiol 2016;7:441.
10. Geng Y, Mosyak L, Kurinov I, et al. Structural mechanism of ligand activation in human calcium-sensing receptor. Elife 2016;5:.
11. Campion KL, McCormick WD, Warwicker J, et al. Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism. J Am Soc Nephrol 2015;26:2163-71.

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