Receptors for PTH and PTHrP: their biological importance and functional properties

Receptors for PTH and PTHrP: their biological importance and functional pro perties. The type 1 receptor (PTH1R) for parathyroid hormone (PTH)and parat hyroid hormone-related peptide (PTHrP) is a G protein-coupled receptor that is highly expressed in bone and kidney and mediates in these tissues the P TH-dependent regulation of mineral ion homeostasis. The PTH1R also mediates the paracrine actions of PTHrP, which play a particularly vital role in th e process of endochondral bone formation. These important functions, the li kely involvement of the PTH1R in certain genetic diseases affecting skeleta l development and calcium homeostasis, and the potential utility of PTH in treating osteoporosis have been the driving force behind intense investigat ions of both the receptor and its peptide ligands. Recent lines of work hav e led to the identification of constitutively active PTH1Rs in patients wit h Jansen's metaphyseal chondrodysplasia, the demonstration of inverse agoni sm by certain ligand analogs, and the discovery of the PTH-2 receptor subty pe that responds to PTH but not PTHrP. As reviewed herein, a detailed explo ration of the receptor-ligand interaction process is currently being pursue d through the use of site-directed mutagenesis and photoaffinity cross-link ing methods; ultimately, such work could enable the development of novel PT H receptor ligands that have therapeutic value in treating diseases such as osteoporosis and certain forms of hypercalcemia.