The calcium‐sensing receptor: one of a kind

Abstract

Daniela Riccardi has always been fascinated with how cells sense changes in their environment and their responses at the molecular and cellular through to whole-organism level. The extracellular calcium-sensing receptor (CaSR) has the unique ability to sample the extracellular milieu and to integrate multiple stimuli into one output, in a manner that is both cell and signal dependent. In most cases this feature is a boon, but it can become a bane when non-physiological CaSR activators hijack this receptor, leading to CaSR overactivation, hence pathology. Since receiving the Wellcome Trust Prize for Excellence in Physiology in 2000, Daniela Riccardi's work has focused on elucidating the physiological roles of the CaSR in non-calciotrophic tissues, on the identification of tissue-specific physiopathological stimuli and on the use of pharmacological modulators of the CaSR to manipulate receptor function in diseases such as vascular calcification and asthma. New Findings r What is the topic of this review?The extracellular calcium-sensing receptor, CaSR, ensures whole-body Ca 2+ homeostasis. Recent developments highlight the importance of the CaSR beyond mineral ion metabolism. This review focuses on novel roles and the use of CaSR-based therapeutics within the vasculature, the gut and the lung. r What advances does it highlight?The ability of the CaSR to act as a multimodal chemosensor has led to the identification of signalling pathways that are ligand and cellular context dependent. Development of cell-specific CaSR modulators is now being harnessed to rescue aberrant CaSR function outside the extracellular Ca 2+ homeostatic system.The extracellular calcium-sensing receptor, CaSR, is the first G protein-coupled receptor found to have an inorganic ion, calcium (Ca 2+ ), as its physiological agonist. It is highly expressed in all organs involved in the regulation of mineral ion metabolism, namely the parathyroid gland, the kidney and bone. The CaSR is the master controller of extracellular Ca 2+ concentration, as highlighted by the evidence that both inherited and acquired mutations in the CASR gene cause disturbances in mineral ion metabolism. CaSR positive allosteric modulators have been successfully employed in the clinic for over a decade to restore CaSR function, which is reduced in hyperparathyroidism secondary to kidney failure, while negative allosteric modulators are currently being tested in patients with hypocalcaemia with hypercalciuria due to gain-of-function CASR mutations. In addition to its expression within the bone-kidney-parathyroid axis, the CaSR can be found in other tissues, including but not limited to the gut, the vasculature and the lung. Here, the CaSR acts as a chemosensor, integrating signals deriving from nutrient availability, salinity, acidification and the presence of ubiquitous polyamines. Knowledge of what these stimuli are and of the cell-specific signalling responses they evoke is crucial to our understanding of the non-calciotropic roles of the CaSR in physiology and how these a...

The role of the calcium-sensing receptor in gastrointestinal inflammation

“…Altered CaSR expression and/or activity is associated not only with disorders of the parathyroid glands, but also with other conditions like vascular calcification, osteoporosis, and neoplasia [29]. A better understanding of the myriad of stimuli for this receptor and of the resulting tissue-specific signaling responses is critical to appreciating the non-calciotropic roles of the CaSR in health and in disease [30]. …”

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

“…Soon it was, therefore, proposed that these compounds could correct the molecular defect caused by inactivating or activating CASR mutations and thus might be useful in the treatment of associated diseases (41,42,55,56).…”

“…The CASR is one of the first GPCRs for which an allosteric activator, the calcimimetic cinacalcet, has been developed and approved for therapeutic use in humans (37,38,39,40) to treat primary and secondary hyperparathyroidism (41,42). In addition, cinacalcet has been used for treatment of hyperparathyroidism related to hereditary vitamin D-resistant rickets (43) and X-linked hypophosphatemia (44).…”

Calcium-sensing receptor in nutrient sensing: an insight into the modulation of intestinal homoeostasis

“…CaSR, a well-conserved and ancient guanine nucleotidebinding protein (G protein)-coupled receptor (GPCR), maintains systemic extracellular Ca 2+ homoeostasis by modulating parathyroid hormone secretion (5,6) . Notably, CaSR plays other crucial roles in the physiology and pathophysiology of cellular functions involved in the growth, development and health of organisms (7)(8)(9) . CaSR can activate various tissue-specific signalling pathways upon agonist or allosteric activator stimulation and thus play critical roles in various biological processes, such as hormone secretion, cell proliferation, cell differentiation, apoptosis, ion channel activity, cell membrane potential regulation and modulation of signalling molecules for gene and protein expression (5,6,10,11) .…”