ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Commun 10, 4693 (2019).

In brief: A specific anion binding site senses moderate changes of inorganic phosphate levels leading to rapid inhibition of CaSR responsiveness and PTH secretion in a murine and human in vitro model system.

Commentary: Phosphate sensing represents a crucial process in the regulation of phosphate homeostasis which remains only partially understood despite ongoing scientific efforts. On a systemic level, the association of inorganic phosphate levels (Pi) and PTH secretion is a well-known phenomenon, but the mechanism of parathyroid phosphate sensing was unclear. With the crystal structure characterisation of CaSR described in 2016, the G-protein coupled receptor revealed multiple phosphate binding sites mainly for stabilization of its inactive state.

Centeno et al. elegantly used in vitro and ex vivo models including freshly isolated human parathyroid cells to study phosphate-specific effects on CaSR signaling. The authors identified a rapid, dose-dependent attenuation of CaSR activity by moderate changes in Pi levels and identified a single residue in an anion-binding site as a crucial site for phosphate-dependent inhibition. The specific characteristics of this phosphate-sensing mechanism might be of particular relevance for patients with chronic kidney disorder by the ability of sensing small deviations in Pi concentrations, the receptor is shifts towards inactive configuration thus increasing PTH expression under hyperphosphatemic condition. Since phosphate levels at the upper end or above the normal range are a common feature of this patient cohort, the response to calcimimetics in the control of secondary hyperparathyroidism might therefore be enhanced by tighter control of serum phosphate levels.

These novel insights mark a new horizon in the understanding of systemic phosphate homeostasis. Further, the role of the described mechanism in the complex interplay between Ca and Phosphate levels, PTH, FGF23/Klotho and calcitriol levels might reveal new perspectives in the understanding of other disorders of mineral metabolism, such as XLH.