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Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome.

Ignacio Portales-CastilloThomas DeanRoss W ChelohaBrendan A CreemerJean-Pierre VilardagaSofya SavranskyAshok KhatriHarald JüppnerThomas J Gardella
Published in: Communications biology (2023)
The parathyroid hormone receptor type 1 (PTH1R) is a G protein-coupled receptor that plays key roles in regulating calcium homeostasis and skeletal development via binding the ligands, PTH and PTH-related protein (PTHrP), respectively. Eiken syndrome is a rare disease of delayed bone mineralization caused by homozygous PTH1R mutations. Of the three mutations identified so far, R485X, truncates the PTH1R C-terminal tail, while E35K and Y134S alter residues in the receptor's amino-terminal extracellular domain. Here, using a variety of cell-based assays, we show that R485X increases the receptor's basal rate of cAMP signaling and decreases its capacity to recruit β-arrestin2 upon ligand stimulation. The E35K and Y134S mutations each weaken the binding of PTHrP leading to impaired β-arrestin2 recruitment and desensitization of cAMP signaling response to PTHrP but not PTH. Our findings support a critical role for interaction with β-arrestin in the mechanism by which the PTH1R regulates bone formation.
Keyphrases
  • binding protein
  • body composition
  • single cell
  • bone marrow
  • bone mineral density
  • mesenchymal stem cells
  • transcription factor
  • protein kinase