2. Academic Validation
  3. Absence of calcium-sensing receptor basal activity due to inter-subunit disulfide bridges

Absence of calcium-sensing receptor basal activity due to inter-subunit disulfide bridges

  • Commun Biol. 2024 Apr 25;7(1):501. doi: 10.1038/s42003-024-06189-3.
Shumin Ma 1,  Xueliang Yin 1,  Jean-Philippe Pin 2,  Philippe Rondard 3,  Ping Yi 4,  Jianfeng Liu 5
Affiliations

Affiliations

  • 1 Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, INSERM, Montpellier, Cedex 5, France.
  • 3 Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, INSERM, Montpellier, Cedex 5, France. philippe.rondard@igf.cnrs.fr.
  • 4 Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China. pingy@hust.edu.cn.
  • 5 Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China. jfliu@mail.hust.edu.cn.
PMID: 38664468 DOI: 10.1038/s42003-024-06189-3
Abstract

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 necessary to limit the agonist effect of Amino acids on CaSR. Furthermore, human genetic mutations deleting these bridges and associated with hypocalcemia result in elevated CaSR constitutive activity. These results highlight the physiological importance of fine tuning the constitutive activity of G protein-coupled receptors.

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