Journal of Molecular Endocrinology

Role of the CaSR, Gα₁₁ and AP2 complex in the regulation of PTH secretion and renal tubular calcium reabsorption. The binding of calcium (red filled-in circle, Ca) to the extracellular bilobed venus fly trap (VFT) domain of the CaSR (grey) results in Gα₁₁ (yellow)-dependent stimulation of phospholipase C-β (PLCβ) (dark blue) activity, which catalyses the formation of inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP₂). An accumulation of IP₃ mediates the rapid release of calcium into the cytosol from intracellular stores, whereas DAG activates the MAPK cascade. These intracellular signalling events lead to a decrease in PTH secretion from the parathyroid chief cell and reduction in renal tubular calcium reabsorption. CaSR cellsurface expression is regulated by agonist-driven insertional signalling (ADIS) (not shown) (Grant et al. 2011) and also by an endocytic complex comprising clathrin, β-arrestin (green) and the AP2 complex (orange), which traffic this GPCR to the endosomal-lysosomal degradation pathway (light blue) or recycle the CaSR back to the cell surface (Breitwieser 2013). Loss- and gain-of-function mutations of the CaSR lead to FHH1 and ADH1, respectively, whereas loss- and gain-of function mutations of the Gα₁₁-subunit are associated with FHH2 and ADH2, respectively. Loss-offunction mutations of the AP2σ-subunit lead to FHH3.