The Bovine Renal Parathyroid Hormone (PTH) Receptor Has Equal Affinity for Two Different Amino Acid Sequences: The Receptor Binding Domains of PTH and PTH-Related Protein Are Located within the 14–34 Region

Abstract

Previous studies examining the interaction of PTH and PTH-related protein (PTHrP) with target tissue have for the most part emphasized the similarity between the two hormones in binding to and activating receptors. This observation that two peptides with limited homology have equal affinities for the same receptor is unusual. In this report we investigated two aspects of PTH/PTHrP-receptor interactions. First, the nonhomologous 14-34 regions of PTH and PTHrP were synthesized and evaluated. Second, hybrid peptides containing the 7-18 fragment of one hormone combined with the 19-34 region of the other hormone were studied to determine whether interactions between these two regions are required for receptor recognition. All four peptides were examined in bovine renal cortical membrane and rat osteosarcoma (ROS 17/2.8) cell PTH-binding and PTH-stimulated adenylate cyclase assays. The results indicate that the receptor-binding domains of PTH and PTHrP lie outside of the 1-13 region, the region containing sequence homology shared by the two hormones, and that two peptides of different amino acid sequence bind with equal affinity to the bovine renal PTH receptor. However, in the absence of the N-terminal region, the rat bone PTH receptor displays a preference for the C-terminal (19-34 sequence) region of PTHrP.

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

“…The function of PTH(1-34) on osteoblastlineage cells for bone formation is mediated through PTHR1, a heterotrimeric G protein-coupled receptor (26) that primarily mediates PTH signaling and then transmits it through protein kinase A (PKA) and PKC intracellular signaling pathways (27,28). The 1-34 amino acid fragments of both PTH and PTHrP contain the functional subdomains for PTHR1 signaling (29,30).…”

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…125 I]PTH(1-34) radioligand to the receptor as effectively as PTH(15-34) fragment (Caulfield et al, 1990). The early supposition that the principal binding domains of PTH and PTHrP adopt similar conformations when binding to the receptor has now largely been confirmed by the recent crystallographic analyses of each of ligand fragment in complex with the same binding portion of the receptor, as discussed further below.…”

Structure-Activity Relation of NH2-terminal Human Parathyroid Hormone Fragments

“…All fragments show the loop region and the COOHterminal helix. His-14 to Leu-28 (loop and COOH-terminal helix) comprises the major part of the receptor binding region that is known to reside within His-14 to Phe-34 (5,6,68). The NH 2 -terminal helix, however, is present only in the in vivo bioactive fragments hPTH-(1-37) and hPTH-(2-37), but not in the inactive fragments hPTH-(3-37) and hPTH-(4 -37) (Table II).…”

“…In addition to the cyclic adenosine monophosphate (cAMP) pathway, involvement of the phosphatidylinositol hydrolysis signaling pathway is postulated for these functions (4). The receptor binding region mediating the calcium regulatory activity is located within sequence His-14 to Phe-34 (5,6). The complete NH 2 -terminal part of hPTH-(1-34) is required for stimulation of the cAMPdependent pathway (4), and the minimum sequence affecting bone and kidney comprises amino acids 2-27 (1,7).…”