Endocrine Abstracts

The calcium-sensing receptor (CaSR) is a critical modulator of mineral homeostasis. This cell-surface class C G-protein coupled receptor binds extracellular calcium, phosphate and amino acids, and is the target of calcimimetic and calcilytic drugs. The CaSR is expressed on the cell surface as a homodimer and is most highly expressed in the parathyroid glands and the thick ascending limb of the Loop of Henle, where it acts to maintain a near-constancy of circulating calcium concentrations by regulating parathyroid hormone (PTH) secretion and urinary calcium excretion, respectively. The other major calcitropic role of the CaSR involves regulating mammary gland PTH related peptide (PTHrP) secretion during lactation. The importance of the CaSR for calcium homeostasis is highlighted by the identification of germline loss- and gain-of-function CaSR mutations, which cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively, and also by the efficacy of CaSR-targeted drugs for the treatment of parathyroid disorders. The CaSR also has non-calcitropic roles and is highly expressed in pancreatic beta-cells, where it regulates insulin secretion and may also influence glucose homeostasis. In addition, abnormal expression or function of the CaSR is implicated in the pathogenesis of chronic lung diseases and also malignancies such as carcinoma of the breast. This has led to CaSR targeted drugs being evaluated for non-calcitropic disorders. Novel strategies such as utilising inhaled calcilytic drugs for asthma may help to minimize adverse effects arising from inappropriate modulation of the CaSR in calcitropic tissues.