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Journal article
Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor
ACS chemical neuroscience, v 19(7), pp 1661-1670
08 Jul 2024
PMID: 38975966
Featured in Collection : Research Supported by Drexel Libraries' OA Programs
Abstract
The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G′s conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 μM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.
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Details
- Title
- Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor
- Creators
- Young-Hoon Ahn (Corresponding Author) - Drexel University, ChemistryNadee N J Matarage Don - Drexel UniversityFnu Rayavarapu Padmavathi - Drexel University, ChemistryTalan D Kasro - Drexel UniversityMd. Rumman U. Zaman - Drexel UniversityHai-Feng (Frank) Ji - Drexel University, Materials Science and EngineeringJeffrey L Ram - Wayne State University
- Publication Details
- ACS chemical neuroscience, v 19(7), pp 1661-1670
- Publisher
- ACS Publications
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Materials Science and Engineering; Chemistry
- Web of Science ID
- WOS:001268150700001
- Scopus ID
- 2-s2.0-85198135703
- Other Identifier
- 991021891515504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology