Extracellular calcium-sensing receptors in the parathyroid gland, kidney, and other tissues

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Abstract
The discovery of the extracellular calcium-sensing receptor, CasR has broadened our understanding of calcium homeostasis and led to the development of new pharmacological agents, calcimimetics, for treating hyperparathyroidism. In the present review, I discuss the function of CasR as well as provide evidence for the presence of additional calcium-sensing mechanisms in the skeleton and possibly other tissues. Inactivating and activating mutations of the CasR respectively cause hereditary hyperparathyroidism, and demonstrate the predominant role of the CasR in controlling parathyroid gland function. Calcimimetics, which increase the sensitivity of CasR to extracellular calcium have been developed to treat secondary and primary hyperparathyroidism. In recent clinical trials in patients with end stage kidney disease, the calcimimetic cinacalcet suppressed parathyroid hormone to a greater degree than conventional therapy with vitamin D analogues without causing hypercalcemia or hyperphosphatemia. CasR receptor also has functions in other tissues, including regulation of renal calcium excretion and calcitonin secretion by thyroidal C-cells, but the presence of redundant sensing mechanisms for extracellular calcium in other tissues, including bone, confounds the assessment of the receptor's function at these sites. Mouse genetic approaches have so far failed to identify any essential, non-redundant role for the calcium-sensing receptor in regulating chondrogenesis or osteogenesis, and have failed to establish a function for the protein outside of the parathyroid gland, kidney, and thyroidal C-cells. Rather, there is evidence for other putative calcium sensing receptor-like mechanisms in osteoblasts that remain to be identified. Sensing of extracellular calcium by CasR is important in regulating calcium homeostasis, but CasR may have vestigial function in various tissues where it is expressed in low abundance. The relative importance of CasR and the novel calcium-sensing mechanisms in mediating response to extracellular calcium in many of these tissues remain to be determined.