Figure 1. Role of the CaSR in Ca²⁺_o homeostasis.

A. The CaSR is highly expressed in the parathyroid glands (grey), which are located adjacent and posterior to the thyroid gland (pink). The parathyroid CaSR detects reductions in Ca²⁺_o, which leads to the release of PTH. PTH acts on the PTH1 receptor (PTH1R) to increase resorption of Ca²⁺ from bone, promote urinary Ca²⁺ reabsorption, and enhance expression of the renal 1-α-hydroxylase (1αOHase) enzyme, which converts the 25-hydroxyvitamin D (25D) precursor metabolite to biologically active 1,25-dihydroxyvitamin D (1,25D). The elevated 1,25D increases absorption of dietary calcium by acting on the intestinal vitamin D receptor (VDR)³. The kidney CaSR acts independently of PTH to regulate urinary Ca²⁺ reabsorption⁶⁰,⁶¹. Increases in Ca²⁺_o and 1,25D concentrations lead to negative feedback on the parathyroid glands, thereby inhibiting further PTH release. B. Nephron segment-specific roles of the CaSR. The CaSR is expressed in the: apical membrane of the proximal tubule (PT), where it regulates 1,25D synthesis and phosphate (Pi) excretion; basolateral membrane of the cortical thick ascending limb (TAL) of the Loop of Henle, and apical and basolateral membranes of the distal convoluted tubule (DCT), where it regulates Ca²⁺ reabsorption; apical and basolateral membranes of the collecting duct (CD), where it regulates H⁺ and water excretion; and juxtaglomerular apparatus (JGA), where it regulates renin secretion⁵⁸,⁶⁴. (+), stimulatory action of CaSR; (-), inhibitory action of CaSR. C. During lactation, the mammary gland CaSR detects reductions in Ca²⁺_o, which leads to increased PTHrP secretion from mammary epithelial cells into the circulation⁹. PTHrP acts on the PTH1R to increase bone resorption, which in turn releases Ca²⁺_o for milk production⁹. Stimulatory and inhibitory actions are indicated by solid lines and dashed lines, respectively.