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Classic endocrine feedback loops ensure the minute-to-minute regulation of blood Ca. Extracellular Ca binds and activates the CaSR on the surface of parathyroid cells. The CaSR is coupled to the G-proteins Gi and Gq/11 and its activation by ECF Ca lead to a decrease in intracellular cAMP and an increase in intracellular calcium and diacyl glycerol. The increase in intracellular Ca leads to a reduction in the release of PTH. Hypocalcemia leads to the opposite sequence of events.

Thus, a decrease in ECF Ca leads to reduced activation of the parathyroid CaSR, which leads to lower intracellular Ca, and an increase in PTH production and secretion (Fig. 2). PTH can rapidly (over the course of minutes) augment Ca reabsorption in the CTAL and DCT of the kidney. PTH then acts on bone, over the course of several hours to days, to enhance osteoclastic bone resorption and liberate both Ca and phosphate from the skeleton. PTH has also been reported to increase the release of FGF23 from mature osteoblasts and osteocytes [37]. There may also be PTH-independent “buffering” of ECF Ca by bone through incompletely understood mechanisms, perhaps involving the CaSR, which rapidly returns ECF Ca to its baseline value following the induction of hypocalcemia [38]. PTH can stimulate the renal conversion of 25(OH)D, to the active sterol 1,25(OH)₂D [39], likely over several hours, which in turn will augment intestinal Ca absorption. More prolonged hypocalcemia and exposure to elevated PTH, may also result in 1,25(OH)₂D-mediated release of Ca and P from bone [40]. The net effect of the increased reabsorption of filtered Ca along the nephron, of the mobilization of Ca from bone, and of the increased absorption of Ca from the gut is to restore the ECF Ca to normal and to inhibit further production of PTH and 1,25(OH)₂D. Additionally, FGF23 can be released from bone by 1,25(OH)₂D [41] and can in turn reduce 1,25(OH)₂D concentrations [42]. FGF23 has also been reported to decrease PTH production, thereby further ensuring that Ca homeostasis is restored [43, 44].

When the ECF Ca is raised into the hypercalcemic range, the opposite sequence of events occurs, that is, PTH secretion is reduced due to the stimulation of the parathyroid CaSR, and renal 1,25(OH)₂D production is decreased. In addition, the elevated Ca per se may stimulate the renal CaSR in the CTAL, thus inducing calciuria. Therefore, the effect of suppressing PTH release and 1,25(OH)₂D synthesis and of stimulating renal CaSR results in reduced renal tubular Ca reabsorption, decreased skeletal Ca release, and decreased intestinal Ca absorption, resulting in the normalization of the elevated ECF Ca.