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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Allosteric modulation of the calcium-sensing receptor
Anders A Jensen1, Hans Bräuner-Osborne
1Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Current Neuropharmacology
|March 24, 2009
Summary
The calcium-sensing receptor (CaR) regulates calcium levels by controlling parathyroid hormone secretion. Synthetic modulators, like cinacalcet, offer new therapeutic strategies for hyperparathyroidism.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- The calcium-sensing receptor (CaR), a G-protein coupled receptor (GPCR), plays a crucial role in maintaining extracellular calcium homeostasis.
- CaR is activated by physiological calcium and magnesium levels and modulated by amino acids.
- Synthetic calcimimetics and calcilytics are allosteric modulators targeting the CaR's 7-transmembrane domain.
Purpose of the Study:
- To elucidate the structure-function relationship of the CaR.
- To explore the therapeutic potential of CaR modulators in calcium-related disorders.
- To highlight the significance of cinacalcet as a proof-of-concept for allosteric GPCR drug development.
Main Methods:
- Characterization of CaR activation and modulation by endogenous and synthetic ligands.
- Analysis of CaR's role in parathyroid hormone (PTH) and calcitonin secretion.
- Clinical evaluation of calcimimetics in hyperparathyroidism.
Main Results:
- Endogenous ligands (Ca2+, Mg2+, amino acids) bind to the amino-terminal domain, while synthetic modulators bind to the 7-transmembrane domain.
- CaR dysfunction contributes to primary and secondary hyperparathyroidism.
- Cinacalcet, a calcimimetic, is approved for treating hyperparathyroidism, demonstrating therapeutic efficacy.
Conclusions:
- The CaR is a critical regulator of calcium balance, with distinct ligand-binding domains.
- Allosteric modulators targeting the CaR represent a significant advancement in treating disorders of calcium metabolism.
- Cinacalcet's success validates the therapeutic strategy of targeting GPCRs with allosteric modulators.
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