ArticleScientific reports2017
Investigating the molecular mechanism of positive and negative allosteric modulators in the calcium-sensing receptor dimer.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Both calcium-sensing receptor intracellular C-terminal domains support homodimer signaling.Molecular pharmacology · 2025Article
- Inosine-5'-monophosphate interacts with the TAS1R3 subunit to enhance sweet taste detection.Food chemistry. Molecular sciences · 2025Article
- The calcium-sensing receptor: a comprehensive review on its role in calcium homeostasis and therapeutic implications.American journal of translational research · 2025Review
- The Role of Ion Channels in Pulmonary Hypertension: A Review.Pulmonary circulation · 2025Review
- Absence of calcium-sensing receptor basal activity due to inter-subunit disulfide bridges.Communications biology · 2024Article
- Cell Surface Calcium-Sensing Receptor Heterodimers: Mutant Gene Dosage Affects CaJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Article
- How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?ACS chemical neuroscience · 2022Article
- Symmetric activation and modulation of the human calcium-sensing receptor.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Biophysical and functional characterization of the human TAS1R2 sweet taste receptor overexpressed in a HEK293S inducible cell line.Scientific reports · 2021Article
- Article
- Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor.Science advances · 2021Article
- Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural Mechanism of Cooperative Regulation of Calcium-Sensing Receptor-Mediated Cellular Signaling.Current opinion in physiology · 2020Article
- International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function.Pharmacological reviews · 2020Review
- Negative allosteric modulators of the human calcium-sensing receptor bind to overlapping and distinct sites within the 7-transmembrane domain.British journal of pharmacology · 2020Article
- Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism.ACS pharmacology & translational science · 2018Article
- Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor signalling pathway.British journal of pharmacology · 2018Review
- The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Allosteric modulators that are targeting the calcium-sensing receptor (CaSR) hold great therapeutic potential, and elucidating the molecular basis for modulation would thus benefit the development of novel therapeutics. In the present study, we aimed at investigating the mechanism of allosteric modulation in CaSR by testing dimers carrying mutations in the allosteric site of one or both of the subunits. To ensure measurements on a well-defined dimer composition, we applied a trans-activation system in which only the specific heterodimer of two loss-of-function mutants responded to agonist. Although one of these mutants was potentiated by a positive allosteric modulator, we showed that receptor activity was further potentiated in a trans-activation heterodimer containing a single allosteric site, however only when the allosteric site was located in the subunit responsible for G protein coupling. On the contrary, preventing activation in both subunits was necessary for obtaining full inhibition by a negative allosteric modulator. These findings correlate with the proposed activation mechanism of the metabotropic glutamate receptors (mGluRs), in which only a single transmembrane domain is activated at a time. CaSR and mGluRs belong to the class C G protein-coupled receptors, and our findings thus suggest that the activation mechanism is common to this subfamily.
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