biostudies-literatureMa SFondation pour la Recherche Médicale (Foundation for Medical Research in France)National Natural Science Foundation of China (National Science Foundation of China)501https://www.ebi.ac.uk/biostudies/studies/S-EPMC11045811biostudies-literatureUnknown7(1)G protein-coupled receptors naturally oscillate between inactive and active states, often resulting in receptor constitutive activity with important physiological consequences. Among the class C G protein-coupled receptors that typically sense amino-acids and their derivatives, the calcium sensing receptor (CaSR) tightly controls blood calcium levels. Its constitutive activity has not yet been studied. Here, we demonstrate the importance of the inter-subunit disulfide bridges in maintaining the inactive state of CaSR, resulting in undetectable constitutive activity, unlike the other class C receptors. Deletion of these disulfide bridges results in strong constitutive activity that is abolished by mutations preventing amino acid binding. It shows that this inter-subunit disulfide link is neCommunications biologyAbsence of calcium-sensing receptor basal activity due to inter-subunit disulfide bridges.PMC110458113107073731371423EQU20230301647032330049Yin XLiu JMa SYi PPin JPRondard PfalseAbsence of calcium-sensing receptor basal activity due to inter-subunit disulfide bridges.G protein-coupled receptors naturally oscillate between inactive and active states, often resulting in receptor constitutive activity with important physiological consequences. Among the class C G protein-coupled receptors that typically sense amino-acids and their derivatives, the calcium sensing receptor (CaSR) tightly controls blood calcium levels. Its constitutive activity has not yet been studied. Here, we demonstrate the importance of the inter-subunit disulfide bridges in maintaining the inactive state of CaSR, resulting in undetectable constitutive activity, unlike the other class C receptors. Deletion of these disulfide bridges results in strong constitutive activity that is abolished by mutations preventing amino acid binding. It shows that this inter-subunit disulfide link is ne2024-01-01T00:00:00Z2024 Apr2026-06-02T08:40:01.491Z2026-05-25T03:06:57.481ZS-EPMC110458113866446810.1038/s42003-024-06189-3