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Toward Defining the Pharmacophore for Positive Allosteric Modulation of PTH1 Receptor Signaling by Extracellular
Brandon H Kim1, Fang I Wang1, Alexey Pereverzev1
1Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry; and Bone and Joint Institute; The University of Western Ontario, London, Canada.
ACS Pharmacology & Translational Science
|April 8, 2020
Summary
Extracellular sugar phosphates, like ribose-5-phosphate, act as positive allosteric modulators for the parathyroid hormone 1 receptor (PTH1R). This finding could lead to new osteoporosis therapeutics by enhancing PTH1R agonist efficacy.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- The parathyroid hormone 1 receptor (PTH1R) is a key target for osteoporosis therapies.
- PTH1R activation involves Gs-protein coupling, adenylyl cyclase stimulation, and β-arrestin recruitment.
- Extracellular ATP and CMP were previously identified as positive allosteric modulators of PTH1R signaling.
Purpose of the Study:
- To investigate the effect of extracellular sugar phosphates on PTH1R signaling.
- To identify the pharmacophore responsible for positive allosteric modulation of PTH1R.
- To explore potential development of novel PTH1R-targeting therapeutics.
Main Methods:
- Utilized luminescence-based assays to monitor cAMP levels and β-arrestin recruitment.
- Tested various extracellular sugar phosphates, including ribose-5-phosphate, on PTH1R signaling.
- Employed UMR-106 rat osteoblastic cells and HEK293H cells expressing human PTH1R.
Main Results:
- Ribose-5-phosphate significantly enhanced PTH-induced adenylyl cyclase activation without intrinsic activity.
- Other sugar phosphates (glucose-1-phosphate, glucose-6-phosphate, etc.) also potentiated PTH-induced signaling.
- Glucose-1-phosphate demonstrated a greater effect than its isomer, glucose-6-phosphate, on PTH1R modulation.
Conclusions:
- Phosphorylated monosaccharides, particularly ribose-5-phosphate, contain the pharmacophore for PTH1R positive allosteric modulation.
- The position of the phosphate group influences the extent of allosteric modulation.
- This knowledge may facilitate the development of improved PTH1R agonists for osteoporosis treatment.
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