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Molecular Endocrinology 13 (5): 670-680
Copyright © 1999 by The Endocrine Society

The (1–14) Fragment of Parathyroid Hormone (PTH) Activates Intact and Amino-Terminally Truncated PTH-1 Receptors

Michael D. Luck, Percy H. Carter and Thomas J. Gardella

Endocrine Unit Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114

Recent mutagenesis and cross-linking studies suggest that residues in the carboxyl-terminal portion of PTH(1–34) interact with the amino-terminal extracellular domain of the receptor and thereby contribute strongly to binding energy; and that residues in the amino-terminal portion of the ligand interact with the receptor region containing the transmembrane helices and extracellular loops and thereby induce second messenger signaling. We investigated the latter component of this hypothesis using the short amino-terminal fragment PTH(1–14) and a truncated rat PTH-1 receptor (r{Delta}Nt) that lacks most of the amino-terminal extracellular domain. The binding of PTH(1–14) to LLC-PK1 or COS-7 cells transfected with the intact PTH-1 receptor was too weak to detect; however, PTH(1–14) dose-dependently stimulated cAMP formation in these cells over the dose range of 1–100 µM. PTH(1–14) also stimulated cAMP formation in COS-7 cells transiently transfected with r{Delta}Nt, and its potency with this receptor was nearly equal to that seen with the intact receptor. In contrast, PTH(1–34) was ~100-fold weaker in potency with r{Delta}Nt than it was with the intact receptor. Alanine scanning of PTH(1–14) revealed that for both the intact and truncated receptors, the 1–9 segment of PTH forms a critical receptor activation domain. Taken together, these results demonstrate that the amino-terminal portion of PTH(1–34) interacts with the juxtamembrane regions of the PTH-1 receptor and that these interactions are sufficient for initiating signal transduction.




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