The demonstration that the rare disorder, familial hypocalciuric hypercalcemia, was caused by inactivating mutations in the gene for the calcium-sensing receptor (CaSR, sometimes referred to as CaR) had two major consequences: it explained the phenotypic expression of the disease, and it initiated an ongoing effort to explain the normal physiologic functions of the receptor. This topic will briefly review our understanding of the function of the CaSR in the parathyroid glands and kidneys and then describe conditions caused by mutations in this gene, particularly familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia (table 1). There is also increasing evidence that abnormalities of the CaSR can be an acquired defect in hyperparathyroidism and hypoparathyroidism.
FUNCTIONS OF THE CALCIUM-SENSING RECEPTOR
The calcium-sensing receptor (CaSR) is expressed in multiple tissues, including the parathyroid glands, kidneys, bone marrow, osteoclasts and osteoblasts, breast, thyroid C-cells, gastrin-secreting cells in the stomach, intestine, some areas of the brain, and others [1-7]. One of its main functions is to regulate calcium balance [1,2,8]. The CaSR senses small changes in the serum ionized calcium concentration. In response to these changes, the CaSR brings about changes in the function of parathyroid glands and kidneys, which are directed at normalizing serum calcium concentration. This receptor is also activated by magnesium and by certain amino acids and therefore may have a role in the cellular response to changes in other constituents of the extracellular environment [9,10].
Parathyroid gland — The CaSR is highly expressed on the surface of the chief cells of the parathyroid glands [1,2]. It permits the parathyroid gland to sense variations in the serum calcium concentration, leading to the desired changes in parathyroid hormone (PTH) secretion. A fall in serum calcium concentration is a potent stimulus to the release of PTH (figure 1). This is an appropriate physiologic response since, via its effects to increase bone resorption, to increase the formation of calcitriol in the kidney and to reduce renal calcium excretion, PTH acts to raise the serum calcium concentration toward normal. Chronic hypocalcemia, acting via the CaSR, has other homeostatically appropriate effects on parathyroid function, including increasing PTH gene expression and stimulating parathyroid cellular proliferation. Conversely, when serum calcium concentration is high, synthesis and secretion of PTH are inhibited. (See "Parathyroid hormone secretion and action", section on 'Actions of PTH'.)
There are clearly PTH-independent roles for the CaSR in maintaining the normally exquisitely tight regulation of serum calcium concentration. Mice lacking both the PTH and CaSR genes develop marked hypercalcemia in response to oral calcium loads, while those lacking only PTH can mount an effective defense against hypercalcemia via the CaSR by upregulating renal calcium excretion and calcitonin secretion . In addition, polymorphisms of the CaSR may underlie some of the variability observed in the serum calcium concentrations in normal subjects [12-14].
Urine calcium excretion — The CaSR is an important regulator of urinary calcium excretion [15-19]. It explains why hypercalcemia reduces calcium and sodium transport in the loop of Henle, with an associated decrease in urinary concentrating ability. Receptors expressed on the basolateral membrane on the cells of the thick ascending limb of the loop of Henle appear to be the major site where this occurs [8,20,21].