Distinct Signaling of Native PTH-related Peptide.

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, PTH and PTHrP . While both peptides induce acute intracellular Ca (iCa ) release, they differ in the location and duration of cAMP signaling. PTH induces sustained cAMP production from PTHR signaling complexes in endosomes, whereas PTHrP induces transient cAMP production derived from ligand-PTHR interactions at the plasma membrane. Although the transient nature of PTHrP signaling has been regarded as a main PTHrP feature, here we demonstrate that PTHrP cannot be considered as an analogue of the native PTHrP . We show that PTHrP triggers sustained cAMP signaling from the plasma membrane without inducing b-arrestin recruitment. Additionally, PTHrP fails to stimulate iCa release. We also show that the molecular basis for signaling differences between PTHrP and native PTHrP are caused by the stabilization of distinct PTHR conformations. These results indicate that native PTHrP displays distinct signaling features from PTHrP and can be considered an endogenous biased agonist for PTHR.