PTH receptor-1 signalling—mechanistic insights and therapeutic prospects

Parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PTHR1) mediates the biological actions of two endogenous ligands, PTH and PTHrP and has key roles in regulating blood calcium levels and tissue developmentPTH and PTHrP interact with PTHR1 through similar, although not identical mechanisms, and preferentially stabilize distinct receptor conformationsCertain structurally distinct PTH and PTHrP ligand analogues, which stabilize distinct receptor conformations, induce altered signalling responses that differ in signal type and durationProlonged signalling by certain PTH ligand analogues correlates temporally with ligand–receptor complexes located in endosomes, which suggests mechanisms of signal generation and termination distinct from those described by traditional G-protein-coupled receptor modelsConsideration of ligand-based mechanisms that control signal duration provide insight into the processes of receptor dysfunction, as wells as guidance for addressing PTHR1-related diseasesIdentification and incorporation of specific structural features that promote or prevent long-lasting biological responses hold promise for the design of treatments for hypoparathyroidism and osteoporosis, respectively