Endosomal PTH Receptor Signaling Through cAMP and Its Consequence for Human Medicine

Abstract

The parathyroid hormone (PTH) type 1 receptor (PTHR) is a medically important G protein-coupled receptor (GPCR) that triggers the cAMP/PKA signaling pathway in kidney and bone cells to regulate calcium ion homeostasis and bone turnover. It has been generally assumed that the production of cAMP mediated by GPCR and its termination take place exclusively at the plasma membrane. Recent studies reveal that the PTHR does not always follow this conventional paradigm. In the new model, PTH induces a prolonged cAMP response that is derived from the internalized ligand–PTHR complex located within endosomes. This model has been recognized as a new paradigm of GPCR signaling for peptide hormones, and the PTHR is a prototypical example. In this chapter we discuss molecular, structural, and cellular mechanisms responsible for this unexpected signaling process and its biological consequences.