Distinct Signaling of Native PTH‐related Peptide

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The parathyroid hormone (PTH) type 1 receptor (PTHR) regulates a variety of key biological processes, including mineral ion and bone homeostasis, through the action of its two natural peptide ligands: PTH and PTH‐related peptide (PTHrP). Particularly, PTHrP is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and bone remodeling. Although mature forms of PTHR ligands consist of 84 and 141/173 amino acids for PTH and PTHrP, respectively, our current understanding on how endogenous PTHR ligands transduce signals through PTHR is largely derived from studies done with the N‐terminal fragments of both peptides, PTH1‐34 and PTHrP1‐36. While both peptides induce acute intracellular Ca2+ (iCa2+) release, they differ in the location and duration of cAMP signaling. PTH1‐34 induces sustained cAMP production from PTHR signaling complexes in endosomes, whereas PTHrP1–36 induces transient cAMP production derived from ligand–PTHR interactions at the plasma membrane. Although the transient nature of PTHrP1‐36 signaling has been regarded as a main PTHrP feature, here we demonstrate that PTHrP1‐36 cannot be considered as an analogue of the native PTHrP1‐141. We show that PTHrP1‐141 triggers sustained cAMP signaling from the plasma membrane without inducing b‐arrestin recruitment. Additionally, PTHrP1‐141 fails to stimulate iCa2+ release. We also show that the molecular basis for signaling differences between PTHrP1‐36 and native PTHrP1‐141 are caused by the stabilization of distinct PTHR conformations. These results indicate that native PTHrP1‐141 displays distinct signaling features from PTHrP1‐36 and can be considered an endogenous biased agonist for PTHR.