The identification and cloning of the calcium-sensing receptor (CaSR)
has led to striking advances in our under-standing of calcium metabolism
and mineral homeostasis both in health and disease. The CaSR is one of
a very large super-family of G-protein coupled receptors (GPCRs), and
it is expressed in a variety of tissues including parathyroid, kidney,
gastrointestinal tract, pancreas, brain and placenta (Physiol Rev
81:239-297, 2001). Signal transduction through the CaSR is now known to
have diverse effects on cell differentiation, cell proliferation and
apoptosis. More specifically, CaSR activity serves to regulate fluid
and electrolyte transport across renal and intestinal epithelia.
Although the functional importance of the CaSR in certain tissues has
yet to be determined, its physiological role is perhaps best understood
in the parathyroid glands (Physiol Rev 81:239-297, 2001).
The CaSR represents the molecular mechanism by which parathyroid cells detect changes in the concentration of extracellular calcium ions and modify parathyroid hormone (PTH) secretion (N Engl J Med 333:234-240, 1995). Short-term variations in PTH secretion that are mediated by the CaSR are the principal mechanism for modulating calcium excretion in the urine and calcium release from bone to maintain blood ionized calcium levels within a very narrow physiological range. Because of its pivotal role in preserving calcium homeostasis, alterations in signal transduction through the CaSR lead to overt disturbances in parathyroid gland function and to distinct clinical disorders of bone and mineral metabolism. Several of these are characterized by parathyroid gland hyperplasia suggesting that the CaSR plays a critical role in cell cycle regulation and in the control of cell proliferation in parathyroid tissue. As a key determinant of PTH secretion, the CaSR represents a novel target for therapeutic interventions and/or pharmacological agents designed to modify parathyroid gland function in certain diseases such as secondary hyperparathyroidism (2oHPT) due to chronic renal failure (Principles in Bone Biology, Academic Press, Inc, 1019-1035, 1996).
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