Chapter Seven - The Calcium-Sensing Receptor in Health and Disease
Section snippets
Structure and Physiological Functions of the CaSR
The most important role of the calcium-sensing receptor (CaSR) is the regulation of calcium metabolism. This function is critical as the calcium ion (Ca2+) regulates a wide range of intracellular and extracellular processes in terrestrial organisms and is one of the principal constituents of bone. Maintenance of adequate and nearly constant concentration of extracellular calcium (∼1.0 mM) is essential for life because it provides an adequate muscle and nerve function and is required for normal
Monitoring CaSR Activity in Living Cells
PTH release in parathyroid glands and calcium homeostasis is the model of choice for CaSR study due to its exquisite sensitivity to changes in extracellular Ca2+. However, the CaSR is expressed in numerous tissues and cell types other than parathyroid glands. Accordingly, CaSR may play important physiopathological roles beyond PTH release and extracellular calcium homeostasis (Breitwieser et al., 2004). Several approaches have been used for detecting the expression of functional CaSR in the
CaSR in Endocrine Pathology
Given the critical role of the CaSR in the regulation of the entire extracellular Ca2+ homeostatic system, alterations in CaSR, its molecular partners, and/or signaling pathways are expected to make quite a significant contribution to imbalances of mineral metabolism. In fact, CaSR knockout (KO) in mice, CaSR mutations in human, as well as the use of calcimimetics and calcilytics have enabled not only the establishment of CaSR's major role in calcium and phosphorus metabolism (Brown, 2013) but,
CaSR in Cardiovascular Physiopathology
Another important organ outside the extracellular Ca2+ homeostatic system, in which CaSR is expressed and may play an important role, is the cardiovascular system. In fact, it has been shown that CaSR is expressed in several cell types in this system including the endothelium, vascular smooth muscle cells (VSMC), and even in the perivascular nerve (Smajilovic et al., 2011). In the past it was demonstrated that dietary intake of Ca2+ may reduce blood pressure (Hatton and McCarron, 1994). Part of
CaSR in Asthma
The CaSR has emerged very recently as a potential asthma therapeutic target. Asthma is characterized by airway hyperresponsiveness, bronchoconstriction, and chronic inflammation. This heterogeneous disease affects over 300 million people worldwide and its prevalence is increasing, especially in developing countries (Bernstein and Levy, 2014). Current treatments for asthma include drugs designed to target not the causes but the symptoms, that is, airway inflammation by corticosteroids, and
CaSR in Alzheimer's Disease
AD is a neurodegenerative disorder associated to a progressive and irreversible loss of memory, cognitive decline, and ultimately dementia. Recent evidence suggest that CaSR could be a direct target for amyloid β peptides, the most likely toxins in AD. Most forms of AD are sporadic and strongly linked to advanced age. However, a small fraction of around 5% of all cases show up earlier in life and are considered familial forms of the disease or familiar Alzheimer's disease (FAD). The most
CaSR in Cancer
The key role of calcium in so many different aspects of cell physiology including cell proliferation, differentiation, and cell death predicts a role for this cation in cancer. However, it has not been until recently that evidence is starting to emerge regarding how Ca2+ dishomeostasis, both intracellular and extracellular, may contribute to cancer development.
Regarding intracellular Ca2+, it has been established that the expression of different molecular players involved in intracellular Ca2+
Acknowledgments
We thank Mr. Milton Jensen for the English proofing of the manuscript. This work and the authors work has been supported by the Ministry of Economy and Competitivity, Spain (grants BFU2012-37146 and BFU2015-70131R to CV and SAF2013-44521-R to CGR) and cofunded by the European fund Feder, the Junta de Castilla y León, Spain (grants BIO/VA46/14 to CV, VA145U13 to LN, BIO/VA11/15 to AR, and BIO/VA36/15 to CGR) and the Instituto de Salud Carlos III, Spain (grant RD12/0042/0026 and the RIC network).
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