Receptors for Parathyroid Hormone (PTH) and PTH-Related Peptide

Abstract

The biological actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) have attracted wider interest in recent years because of the rapid advances in the study of the developmental biology of bone in which PTHrP and its receptor play a major role, as well as demonstration of the therapeutic potential of PTH in fracture prevention in osteoporosis. One principal receptor, the type-1 PTH/PTHrP receptor (PTH1R), is the chief mediator of both the homeostatic actions of PTH and the paracrine actions of PTHrP on endochondral bone development. This receptor interacts equivalently with the amino-terminal domains of PTH and PTHrP. Additional receptors clearly interact differentially with PTH versus PTHrP and/or with regions of the two ligands other than their amino-terminal domains. The recombinant PTH-1 receptor (PTH1R) interacts equivalently with PTH and PTHrP and activates at least two distinct second messenger pathways, adenylate cyclase/protein kinase A (AC/PKA) and phospholipase C/protein kinase C (PLC/PKC). The PTH-1 receptor belongs to a distinct family of G protein-coupled receptors (GPCR), called class II (or family B) receptors. The first cDNAs encoding mammalian PTH-1 receptors were isolated through expression cloning techniques from cell lines that had been widely used in classical PTH/FFH receptor studies. Current data indicate that the PTH receptor interacts with multiple regions of PTH peptide ligands and these contacts establish binding affinity and/or promote receptor activation. PTH(1–34) and PTHrP(1–34) bind to and activate the PTH-1 receptor with affinities and potencies in the low nanomolar range. The PTH-2 receptor subtype was initially identified through hybridization cloning methods in a human brain cDNA library. At the amino acid level, this receptor is 51% identical to the human PTH-1 receptor. The human PTH-2 receptor responds to PTH but not to PTHrP, whereas the rat PTH-2 receptor responds to neither PTH nor PTHrP.