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 Ca 2+ homeostasis in bone remodeling, during which Ca 2+ 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 Ca 2+ . However, PTHrP(1–36), another truncated endogenous agonist for PTH1R, does not show this Ca 2+ effect. Mutations of Glu19 and Glu22 in PTH(1–34) that are not conserved in PTHrP(1–36) largely abolished the Ca 2+ effect. The results support that PTH(1–34) not only activates PTH1R but also uniquely senses Ca 2+ . 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.