Novel regulatory aspects of the extracellular Ca2+-sensing receptor, CaR

Abstract

The capacity to sense and adapt to changes in environmental cues is of paramount importance for every living organism. From yeast to man, cells must be able to match cellular activities to growth environment and nutrient availability. Key to this process is the development of membrane-bound systems that can detect modifications in the extracellular environment and to translate these into biological responses. Evidence gathered over the last 15 years has demonstrated that many of these cell surface "sensors" belong to the G protein-coupled receptor superfamily. Crucial to our understanding of nutrient sensing in mammalian species has been the identification of the extracellular Ca(2+)/cation-sensing receptor, CaR. CaR was the first ion-sensing molecule identified in man and genetic studies in humans have revealed the importance of the CaR in mineral ion metabolism. Latter, it has become apparent that the CaR also plays an important role outside the Ca(2+) homeostatic system, as an integrator of multiple environmental signals for the regulation of many vital cellular processes, from cell-to-cell communication to secretion and cell survival/cell death. Recently, novel aspects of receptor function reveal an unexpected role for the CaR in the regulation of growth and development in utero.

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Recent reports clearly point to a role for the CaSR as a regulator of early development and as a guardian of the homeostatic balance between proliferation and differentiation in adults [19,68,70,71,73,75,89,92]. The identification of CaSR mutations that cause FHH and hypocalcemia [93][94][95][96][97][98], and the recent discoveries implicating the dysregulation of CaSR signaling in many other diseases [99,[113][114][115][119][120][121][122][123][124], position the CaSR as a broad therapeutic target.…”

“…The CaSR is highly expressed in the developing fetus, with the highest expression levels found in the central and peripheral nervous system, heart, lung and cartilage [68]. The developing fetus is hypercalcemic compared with the adult, with significantly higher levels of extracellular calcium found in cord blood as compared with maternal blood [69].…”

Calcium, Ca2+-Sensing Receptor and Breast Cancer

“…The metastasis of breast cancer cells to bone result in osteolysis and lead to the release of large quantities of Ca 2+ into the bone microenvironment (45,46). This Ca o 2+ can be a primary signaling molecule and act through the CaR that directly regulates multiple signaling pathways involved in breast cancer cell growth, proliferation, differentiation, apoptosis and migration (58,59), and through the Ca 2+ channels which elevate intracellular Ca 2+ (Ca i 2+ ) levels to modulate Ca 2+ -dependent proteins (60).…”

Functional expression of the multimodal extracellular calcium-sensing receptor in pulmonary neuroendocrine cells

“…The CaSR belongs to group C of the G-protein-coupled receptor superfamily (GPCRs) and has been demonstrated to be sensitive to a variety of metabolic signals including di-and trivalent cations (Ca 2+ , Mg 2+ , metals belonging to the lanthanides series such as La 3+ , etc. ), pH, ionic strength, aromatic amino acids (L-Phe, LTrp) and polyamines such as spermine (for reviews, see Chang and Shoback, 2004;Riccardi et al, 2009;Riccardi and Kemp, 2012). Genetic studies in humans have shown that the best documented role of the CaSR is in systemic homeostasis of extracellular free ionized Ca 2+ concentration [Ca 2+ ] o through the regulation of parathyroid hormone secretion by the parathyroid glands (Brown and MacLeod, 2001;Conigrave et al, 2000).…”

“…Genetic studies in humans have shown that the best documented role of the CaSR is in systemic homeostasis of extracellular free ionized Ca 2+ concentration [Ca 2+ ] o through the regulation of parathyroid hormone secretion by the parathyroid glands (Brown and MacLeod, 2001;Conigrave et al, 2000). However, expression of the CaSR has been reported in many other specialized cells and tissues that are not primarily involved in [Ca 2+ ] o homeostasis, such as in the brain, skin and lungs, suggesting that the receptor might be involved in cellular functions other than divalent cation homeostasis (Hebert et al, 2004;Riccardi et al, 2009;Yano et al, 2004). The CaSR has been reported to be expressed in cells of the diffuse neuroendocrine system, such as endocrine pancreatic cells (Gray et al, 2006), intestinal cholecystokinin secreting cells (Wang et al, 2011), and in a subset of innervated sensory epithelial cells in taste buds (San Gabriel et al, 2009).…”