THE EXTRACELLULAR Ca2+-SENSING RECEPTOR: Central Mediator of Systemic Calcium Homeostasis

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Abstract
▪ Abstract The cloning of the G protein-coupled, extracellular calcium (Ca2+o)-sensing receptor (CaR) has identified a central mediator of the mechanism governing systemic Ca2+o homeostasis. This system enables organisms to adapt successfully to wide variations in dietary Ca2+o intake while maintaining near constancy of Ca2+o. Whereas discussions of Ca2+o homeostasis have generally focused on the key role of Ca2+o-elicited changes in parathyroid hormone secretion, the presence of the CaRs in effector tissues of this system enables direct regulation of processes (e.g. renal tubular Ca2+ reabsorption and possibly bone formation and resorption) that add additional layers of homeostatic control. As we understand more about how the CaR regulates these tissues, we may find that it participates in other processes relevant to mineral ion homeostasis, including the control of the 1-hydroxylation and activation of vitamin D3 or reabsorption of phosphate in the renal proximal tubule. Regardless, the remarkable sensitivity of the CaR to small changes in Ca2+o allows adjustments in the response of the Ca2+o homeostatic system to increases or decreases in the intake of dietary Ca2+, for instance, that cause barely detectable alterations in Ca2+o. Furthermore, the CaR likely participates in coordinating interactions among several different homeostatic control systems (including those for water, Mg2+o, Na+, extracellular volume, and/or blood pressure), despite the fact that these systems are often considered to function largely independently of mineral ion metabolism.