Parathyroid Hormone Senses Extracellular Calcium To Modulate Endocrine Signaling upon Binding to the Family B GPCR Parathyroid Hormone 1 Receptor.

Parathyroid hormone (PTH) binds to a family B G protein coupled receptor, parathyroid hormone 1 receptor (PTH1R). One of its functions is to regulate Ca²⁺ homeostasis in bone remodeling, during which Ca²⁺ can reach up to 40 mM. A truncated version of PTH, PTH(1-34), can fully activate PTH1R and has been used for osteoporosis treatments. Here, we used fluorescence anisotropy to examine the binding of PTH(1-34) to PTH1R purified in nanodiscs (PTH1R-ND) and found that the affinity increases 5-fold in the presence of 15 mM Ca²⁺. However, PTHrP(1-36), another truncated endogenous agonist for PTH1R, does not show this Ca²⁺ effect. Mutations of Glu19 and Glu22 in PTH(1-34) that are not conserved in PTHrP(1-36) largely abolished the Ca²⁺ effect. The results support that PTH(1-34) not only activates PTH1R but also uniquely senses Ca²⁺. This dual function of a peptide hormone is a novel observation that couples changes in extracellular environment with endocrine signaling. Understanding this can potentially reveal the complex role of PTH signaling in bone remodeling and improve the PTH(1-34) treatment for osteoporosis.

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