Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion

Abstract

Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD). The calcium-sensing receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism. Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR. Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a receptor-mediated action. The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion.

Intestinal epithelial ablation of Pit‐2/Slc20a2 in mice leads to sustained elevation of vitamin D3 upon dietary restriction of phosphate

“…In turn, upregulation of NaPi-IIa and NaPi-IIc is the renal response to lower plasma levels of PTH and FGF-23, two phosphaturic hormones synthetized by the parathyroid gland and osteocytes/osteoblast, respectively, in response to high plasma Pi. 31,32,[37][38][39][40] Reductions in phosphaturia and plasma PTH/FGF-23 as well as upregulation of NaPi-IIa/NaPi-IIc were comparable in both genotypes fed on low Pi. In contrast to our data, while comparable reductions in phosphaturia and plasma PTH were also reported in mice with full depletion of Pit-2 and their wild-type counterparts fed low Pi, FGF-23 failed to adapt in mutant mice.…”

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging

“…The transport-independent P i -sensing process might involve co-receptors: for example, FGFR1 [ 48 ] and the CASR [ 196 ]. It is also possible that P i directly binds and inhibits the CASR [ 196 , 197 ]. Finally, there is recent evidence that intracellular P i stimulates the synthesis of 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (IP7) or 1,5-bisdiphosphoinositol 1,2,3,4-tetrakisphosphate (IP8), which are molecules that signal cellular P i sufficiency and stimulate P i efflux via Xenotropic and polytropic retrovirus receptor 1 ( XPR1 ) [ 198 , 199 , 200 , 201 ].…”

“…Lastly, crystallographic studies showed the binding of P i to the CASR [ 196 , 197 ]. The CASR is highly expressed in the parathyroid glands and distal convoluted renal tubules, and it inhibits PTH secretion by the parathyroids and the reabsorption of calcium from the urine upon the binding of calcium [ 210 ].…”

Persistent Hypocalcemia after Thyroidectomy Stabilized with Magnesium

“…Deficiency of PTH also causes hyperphosphatemia, owing to an increase in the renal tubular reabsorption of phosphate (10). Hyperphosphatemia is relevant since, by itself, is related to long-term complications seen in hypoparathyroidism such as central nervous system calcifications, and directly diminish PTH secretion by altering the response of the calcium-sensing receptor (17,18).…”