Parathyroid hormone (PTH) receptor (PTHR) is a G protein–coupled receptor (GPCR) that controls vitamin D, Ca2+, and bone homeostasis by stimulating cAMP production at the plasma membrane and at endosomes after β-arrestin–dependent internalization. White et al. generated a synthetic PTH derivative (PTH7d) that inhibited β-arrestin coupling to PTHR, thereby leading to sustained cAMP production at the cell surface. Comparison of cellular and organismal responses to wild-type PTH, PTH7d, or a PTH analog that elicits sustained endosomal signaling demonstrated that the biological outcome was determined by the subcellular location of PTHR activity. These findings suggest that biological responses elicited by other GPCRs that are active at intracellular compartments may show a similar dependence on the location of signaling.
