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

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.