Chapter Seven - The Calcium-Sensing Receptor in Health and Disease

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Abstract

The extracellular calcium-sensing receptor (CaSR) is a unique G protein–coupled receptor (GPCR) activated by extracellular Ca2+ and by other physiological cations including Mg2+, amino acids, and polyamines. CaSR is the most important master controller of the extracellular Ca2+ homeostatic system being expressed at high levels in the parathyroid gland, kidney, gut and bone, where it regulates parathyroid hormone (PTH) secretion, vitamin D synthesis, and Ca2+ absorption and resorption, respectively. Gain and loss of function mutations in the CaSR are responsible for severe disturbances in extracellular Ca2+ metabolism. CaSR agonists (calcimimetics) and antagonists (calcilytics) are in use or under intense research for treatment of hyperparathyroidism secondary to kidney failure and hypocalcemia with hypercalciuria, respectively. Expression of the CaSR extends to other tissues and systems beyond the extracellular Ca2+ homeostatic system including the cardiovascular system, the airways, and the nervous system where it may play physiological functions yet to be fully understood. As a consequence, CaSR has been recently involved in different pathologies including uncontrolled blood pressure, vascular calcification, asthma, and Alzheimer's disease. Finally, the CaSR has been shown to play a critical role in cancer either contributing to bone metastasis and/or acting as a tumor suppressor in some forms of cancer (parathyroid cancer, colon cancer, and neuroblastoma) and as oncogene in others (breast and prostate cancers). Here we review the role of CaSR in health and disease in calciotropic tissues and others beyond the extracellular calcium homeostatic system.

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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