PTH Receptor

The parathyroid hormone (PTH) type 1 receptor (PTHR) is expressed in many tissues, primarily in bone (osteoblasts and osteocytes), the kidney (proximal and distal tubules), and mammary glands. PTHR is indispensable for maintaining normal Ca2+, phosphate, and active vitamin D levels in blood as well as extracellular fluids in response to PTH. The receptor also regulates growth and development in various tissues such as bone and mammary glands in response to PTH-related peptide (PTHrP). Additionally, PTH and PTHrP are implicated in bone remodeling processes, mediating both anabolic and catabolic effects, but the synthetic N-terminal PTH(1–34) fragment stimulates more prolonged increases in serum levels of 1,25-dihydroxy-vitamin-D, calcium, and bone resorption markers than does PTHrP, when the ligands are injected by continuous infusion. Despite exerting distinct physiological functions, PTH and PTHrP mediate their biological effects via identical heterotrimeric G protein (Gabg) pathways involving primarily Gs/cAMP/protein kinase A (PKA) and Gq/PLC/Ca2+/PKC signaling, and also G12/13/RhoA/phospholipase D and the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase, ERK1/2) signaling cascades. 
These distinct biological effects are attributed to the ability of the PTHR to adopt two distinct active conformations that differ markedly in signaling duration and localization, termed RG and R0. Ligands selective for the G protein-dependent RG state give rise to only transient cAMP production that is confined to the cell surface due to the rapid action of cAMP-specific phosphodiesterases and ligand–receptor internalization mediated by b-arrestinas. Conversely, ligands that bind efficiently to the G protein-independent R0 state promote both acute cAMP responses at the plasma membrane and sustained cAMP generation originating from active signaling complexes that remain stable within endosomal compartments.


1.Sutkeviciute I, et al. Trends Endocrinol Metab. 2019;30(11):860–874.