The Calcium-Sensing Receptor Beyond Extracellular Calcium Homeostasis: Conception, Development, Adult Physiology, and Disease

Abstract

The extracellular calcium-sensing receptor (CaSR) is the first identified G protein-coupled receptor to be activated by an ion, extracellular calcium (Ca(2+)). Since the identification of the CaSR in 1993, genetic mutations in the CaSR gene, and murine models in which CaSR expression has been manipulated, have clearly demonstrated the importance of this receptor in the maintenance of stable, free, ionized Ca(2+) concentration in the extracellular fluids. These functions have been extensively reviewed elsewhere. However, the distribution pattern and expression of the CaSR in lower vertebrates strongly suggest that the CaSR must play a role that is independent of mineral cation metabolism. This review addresses the involvement of the CaSR in nutrient sensing; its putative and demonstrated functions during conception, embryonic development, and birth; and its contributions to adult physiology and disease, with reference to CaSR-based therapeutics. Recent ongoing developments concerning the role of the CaSR in stem cell differentiation are also reviewed.

Activation of the calcium-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane

“…Numerous observations support a pivotal role of the CaSR during the ontogeny of various organs and tissues, including the kidney, the lung, the gastro-intestinal tract, the nervous system and the bone (Riccardi and Kemp, 2012). During mouse development, CaSR immunoreactivity can be widely detected as early as embryonic day 11.5.…”

“…CaSR signaling is mediated through several heterotrimeric (G q/11 , G i/o and G 12/13 ) and small molecular weight G proteins that regulate intracellular second messengers, lipid and protein kinases, and transcription factors (Riccardi and Kemp, 2012). The complexity of CaSR signaling is partly linked to the large variety of ligands that bind to the CaSR and to the diversity of cell types expressing this receptor.…”

“…Interestingly, the CaSR has been identified in numerous tissues and cells that are not directly involved in Ca 2+ homeostasis, in which its role remains unclear (Magno et al, 2011;Riccardi and Kemp, 2012). All along the gastro-intestinal tract, the CaSR participates in nutrient sensing, hormone and fluid secretion, and cell differentiation and apoptosis (Gama et al, 1997).…”

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

“…1 Its function has been shown to be crucial for many physiologic processes, including sperm generation, embryonic development, Ca ++ metabolism, neuronal excitability, etc., and underlie various diseases, such as hyper-and hypoparathyroidism, kidney stones, osteoporosis, Alzheimer disease, epilepsy, etc. 30 The classic CaSR signaling pathway involves its binding to the G proteins-G q/11 , G i , and G 12/13 -that, in turn, stimulate the phospholipase C, producing diacylglycerol and inositol 1,4,5-trisphosphate and increasing intracellular Ca ++ levels. 3 The calcineurin-NFAT pathway, a canonical intracellular Ca ++ signaling mechanism, responds to changes in intracellular Ca ++ by turning on or off a variety of genes in different tissues.…”

Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor

“…These include contributions to the control of epithelial transport, hormone secretion, and even cell fate (review: [7]). …”