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.
Molecular mechanisms mediating tonic secretion of parathyroid hormone
(PTH) in response to hypocalcemia and hyperparathyroidism (HPT) are unclear.
Here we demonstrate increased heterocomplex formation between the
calcium-sensing receptor (CaSR) and metabotropic GABA
B1
receptor
(GABA
B1
R) in hyperplastic parathyroid glands (PTGs) of patients
with primary and secondary HPT. Targeted ablation of GABA
B1
R or
glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcemia and
hypoparathyroidism and prevents PTH hypersecretion in PTGs cultured from mouse
models of hereditary HPT and dietary calcium-deficiency. Co-binding of
CaSR/GABA
B1
R complex by baclofen and high extracellular calcium
blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured
cells and promotes PTH secretion in cultured mouse PTGs. These results combined
with the ability of PTG to synthesize GABA support a critical autocrine action
of GABA/GABA
B1
R in mediating tonic PTH secretion of PTGs and ascribe
aberrant activities of CaSR/GABA
B1
R heteromer to HPT.
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