Abstract
The calcium (Ca2+)-sensing receptor (CaR) belongs to family C of the G-protein coupled receptors (GPCRs). The receptor is activated by physiological levels of Ca2+ (and Mg2+) and positively modulated by a range of proteinogenic L-α-amino acids. Recently, several synthetic allosteric modulators of the receptor have been developed, which either act as positive modulators (termed calcimimetics) or negative modulators (termed calcilytics). These ligands do not activate the wild-type receptor directly, but rather shift the concentration-response curves of Ca2+ to the left or right, respectively. Like other family C GPCRs, the CaR contains a large amino-terminal domain and a 7-transmembrane domain. Whereas the endogenous ligands for the receptor, Ca2+, Mg2+ and the L-α-amino acids, bind to the amino-terminal domain, most if not all of the synthetic modulators published so far bind to the 7-transmembrane domain. The most prominent physiological function of the CaR is to maintain the extracellular Ca2+ level in a very tight range via control of secretion of parathyroid hormone (PTH). Influence on e.g. secretion of calcitonin from thyroid C-cells and direct action on the tubule of the kidney also contribute to the control of the extracellular Ca2+ level. This control over PTH and Ca2+ levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. The perspectives in CaR as a therapeutic target have been underlined by the recent approval of the calcimimetic cinacalcet for the treatment of certain forms of primary and secondary hyperparathyroidism. Cinacalcet is the first clinically administered allosteric modulator acting on a GPCR, and thus the compound constitutes an important proof-of-concept for future development of allosteric modulators on other GPCR drug targets.
Highlights
Calcium (Ca2+) is an essential intracellular messenger and a mediator of a wide range of important physiological and pathophysiological cellular processes
The receptor is an attractive target for the treatment of several disorders, and the therapeutic prospects in calcium-sensing receptor (CaR) ligands have been underlined by the recent introduction of cinacalcet (Sensipar and Mimpara in USA and Europe, respectively) in the clinical treatment of uremic secondary hypercalcemia parathyroidism and parathyroid cancer [10, 76]
In recent years the perception of CaR as a metabolic sensor has been substantiated and further expanded by the realization that CaR signalling is potentiated by several L--amino acids and by the recent cloning of a related G-protein coupled receptors (GPCRs), GPRC6A, which mediates the signalling of L--amino acids and divalent cations [13, 17, 45, 61, 78]
Summary
Calcium (Ca2+) is an essential intracellular messenger and a mediator of a wide range of important physiological and pathophysiological cellular processes. Many of the published synthetic allosteric modulators of the CaR have been shown to target the 7TM of the receptor [30, 32, 36, 48, 59, 60], and the residues involved in the binding of the calcilytics NPS 2143 and Calhex 231 and the calcimimetics NPS R-568 and calindol have been outlined in further detail in mutagenesis studies based on homology models of the 7TM of CaR built using the crystal structure of the family A GPCR rhodopsin as template (Fig. 1A) [48, 59, 60].
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