ESPE Abstracts

The calcium-sensing receptor (CaSR) is the master regulator of calcium homeostasis. This class C G-protein coupled receptor binds extracellular calcium and phosphate, 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 renal thick ascending limb, where it acts to maintain a near-constancy of plasma calcium concentrations by regulating parathyroid hormone (PTH) secretion and urinary calcium excretion, respectively. The other major calcitropic role of the CaSR involves regulating secretion of parathyroid hormone related peptide (PTHrP) from the mammary gland during lactation. The importance of the CaSR for calcium homeostasis has been demonstrated 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 drugs targeting the CaSR for the treatment of parathyroid disorders. The CaSR also has non-calcitropic physiological roles and is highly expressed in the pancreatic islets, where it regulates insulin secretion and may potentially influence glucose homeostasis. In addition, abnormal expression or function of the CaSR is implicated in the pathogenesis of asthma 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.