Calcium-sensing receptor in physiology and in calcitropic and non-calcitropic diseases

The Ca 2+ -sensing receptor (CaSR) is a dimeric family C G-protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and kidneys, and signals via G-proteins and beta-arrestin. The CaSR plays a pivotal role in bone and mineral metabolism by regulating parathyroid hormone secretion, urinary Ca 2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss- and gain-of-function CaSR mutations, which cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by alterations in parathyroid CaSR expression, which contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca 2+ homeostasis, where it has non-calcitropic roles that include lung and neuronal development, vascular tone, gastro-intestinal nutrient sensing, secretion of insulin and entero-endocrine hormones, and wound healing. Furthermore, abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma, but increase the malignant potential of prostate and breast cancers. This review will discuss these physiological and pathophysiological roles of the CaSR. cardiovascular diseases, asthma, Alzheimer’s disease, and breast and colon cancer 9,14-16 . This review focuses on the evolutionary origins, structure and signalling pathways of the CaSR, together with the roles of the CaSR in calcitropic and non-calcitropic diseases. Many of these aspects were discussed at the Third International Symposium on the Ca 2+ -Sensing Receptor (Florence, May 2017), which brought together researchers who are studying these basic, translational and clinical aspects of CaSR physiology and pathophysiology. brain injury that the stoichiometry of these complexes is altered with upregulation of CaSR expression and down regulation of GBR1, which potentiates ischaemic neuronal death 195 . These studies also revealed that calcilytic treatment in mice with brain injury was neuroprotective and improved learning and memory retention 45 . CaSR mutations have been reported in patients with epilepsy 196 , and in vitro studies of a CaSR Arg898Gln mutation, which co-segregated with