Fig. 1: CaSR has very low constitutive activity.

a Schematic diagram of CaSR activation mechanism. In CaSR, each subunit is composed of a VFT formed of two lobes, upper (LB1) and lower (LB2) lobe, that form Ca²⁺ and L-AAs binding site, a cysteine-rich domain (CRD) and a transmembrane domain (7TM) responsible for G protein activation. The two protomers are covalently linked through the two pair of inter-subunit disulfide bridges in the top of VFT. L-AAs act as pure-PAMs without direct agonist effect but could stabilizes the closed state of VFT. The active state can only be achieved by Ca²⁺ binding. b In both HA-tagged CaSR and mGluR5, basal inositol monophosphate (IP₁) accumulation is proportional to the amount of receptors at the cell surface measured by ELISA. Data are mean ± SD from a typical experiment performed in triplicates (n = 3). c Basal IP₁ accumulation for the indicated class C GPCRs. Data are mean ± SEM and normalized to the maximum response of each receptor (n = 3, 20 mM CaCl₂ for CaSR, 1 mM glutamate for mGluR2 and mGluR5, 100 μM GABA for GABA_BR and 100 mM L-Ala with 20 mM CaCl₂ for GPRC6A). d Model showing location of autosomal dominant hypocalcemic (ADH) associated mutations in the CaSR VFT active structure (PDB: 7DTV). ADH mutations are highlighted as red spheres (α carbon). e Schematic and structure (PDB: 7M3E) showing the four main VFT dimer interface in CaSR.