RAAS System ecreased to 2.6 mmol/L, and PTH decreased to 4.6 pmol/L. Although a natural amelioration of the severity of the disease was possible, we were not willing to try a drug holiday. Currently, little is known about the use of calcimimetics in NPHT. Rus et al15 characterized in vitro 7 mutations of the CasR in familial benign hypocalciuric hypercalcemic patients. They showed that NPS R 568, an analog of cinacalcet, improves the signal of the mutant CasR in 4 cases out of 7. A recently published case report also describes a normalization of PTH and calcium under cinacalcet in a child with familial benign hypocalciuric hypercalcemia.16 In our patient, a mutation was found in the extracellular domain with the replacement of an arginine by a histidine. This mutation should not change the chemical characteristics of the region, but it could modify the steric shape of the extracellular domain, leading to calciumbinding difficulties. In this mutation, cinacalcet seemed to besuccessfulandwasable to normalize PTH and Procollagen C Proteinase calcium serum levels. More than 200 mutations of the CaSR are described in NPHT, and it is difficult to predict which will respond to cinacalcet therapy.
However, it seems reasonable and worth trying as an alternative to Dopamine Receptor surgery or while waiting for surgery. The extracellular calcium sensing receptor is a family CGprotein coupled receptor that regulates serum Ca2 levels through negative control of PTH release and renal calcium reabsorption. The CaSR was first isolated from bovine parathyroid glands and has since been identified in thyroid C cells, kidneys, and bone as well as nonsystemic Ca2 homeostatic tissues, including vascular smooth muscle, lungs, central nervous system, keratinocytes, tongue epithelial cells, pancreas, liver, stomach, and intestine. Unlike most other GPCRs, the functional diversity displayed by the CaSR is not attributable to distinct receptor subtypes, of which there are none, the relatively rare instances of CaSR splice variants are also unlikely to account for its numerous functional roles. Moreover, the CaSR is one of a minority of GPCRs activated by multiple endogenous ligands, such as Etoposide extracellular Ca2, Mgo 2, and other multivalent cations, including basic polypeptides and polyamines.
Accordingly, the different ligands of the CaSR may stabilize unique receptor conformations, each with itsowncomplement of signaling pathways. This phenomenon has been referred to as stimulus bias, functional selectivity, ligand directed signaling, or biased agonism. The concept of conformational plasticity is also supported by the CaSRs sensitivity to modulation by changes in extracellular pH, ionic strength, or endogenous allosteric ligands, such as L amino acids and glutamyl peptides. This has also been exploited through the discovery and use of synthetic positive and negative allosteric modulators. Indeed, the calcimimetic, cinacalcet, represents the first modulator of a GPCR to make it to the clinic on the basis of an allosteric mode of action, being Food and Drug Administration/ European Medicines Agency approved for the treatment of secondary hyperparathyroidism in chronic kidney disease patients undergoing dialysis and for hypercalcemia arising in the context of primary hyperparathyroidism due to parathyroid cancer.