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

• Published in: Communications biology 2023-06, Vol.6 (1), p.599-16, Article 599
• Main Authors: Portales-Castillo, Ignacio, Dean, Thomas, Cheloha, Ross W., Creemer, Brendan A., Vilardaga, Jean-Pierre, Savransky, Sofya, Khatri, Ashok, Jüppner, Harald, Gardella, Thomas J.
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/31; 14; 14/10; 631/80/86; 692/163/2743/316; 9/10; 96; 96/1; 96/10; 96/109; 96/95; Arrestin; Biology; Biomedical and Life Sciences; Bone growth; Calcium homeostasis; Cyclic AMP; Homeostasis; Life Sciences; Mineralization; Mutation; Osteogenesis; Parathyroid hormone; Parathyroid Hormone - metabolism; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - metabolism; Receptor, Parathyroid Hormone, Type 1 - chemistry; Receptor, Parathyroid Hormone, Type 1 - genetics; Receptor, Parathyroid Hormone, Type 1 - metabolism; Receptors, G-Protein-Coupled; Signal Transduction - physiology
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04966-0

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. Three mutations in parathyroid hormone receptor type 1 which are present in patients with Eiken syndrome are shown to influence cAMP signaling and β-arrestin recruitment via gain-of-function effects.