Tuberoinfundibular peptide 39 binds to the parathyroid hormone (PTH)/PTH-related peptide receptor, but functions as an antagonist

K. B. Jonsson, M. R. John, R. C. Gensure, T. J. Gardella, H. Jüppner

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The tuberoinfundibular peptide TIP39 [TIP-(1-39)], which exhibits only limited amino acid sequence homology with PTH and PTH-related peptide (PTHrP), stimulates cAMP accumulation in cells expressing the PTH2 receptor (PTH2R), but it is inactive at the PTH/ PTHrP receptor (PTH1R). However, when using either 125I-labeled rat [Nle8,21,Tyr34]PTH-(1-34)amide (rPTH) or 125I-labeled human [Tyr36] PTHrP-(1-36)amide [PTHrP-(1-36)] for radioreceptor studies, TIP-(1-39) bound to LLCPK1 cells stably expressing the PTHIR (HKrk-B7 cells), albeit with weak apparent affinity (243 ± 52 and 210 ± 64 nM, respectively). In comparison to the parent peptide, the apparent binding affinity of TIP-(3-39) was about 3-fold higher, and that of TIP-(9-39) was about 5.5-fold higher. However, despite their improved IC50 values at the PTH1R, both truncated peptides failed to stimulate cAMP accumulation in HKrk-B7 cells. In contrast, the chimeric peptide PTHrP-(1-20)/TIP-(23-39) bound to HKrk-B7 cells with affinities of 31 ± 8.2 and 11 ± 4.0 nM when using radiolabeled rPTH and PTHrP-(1-36), respectively, and it stimulated cAMP accumulation in HKrk-B7 and SaOS-2 cells with potencies (EC50, 1.40 ± 0.3 and 0.38 ± 0.12 nM, respectively) and efficacies (maximum levels, 39 ± 8 and 31 ± 3 pmol/well, respectively) similar to those of PTH-(1-34) and PTHrP-(1-36). In both cell lines, TIP-(9-39) and, to a lesser extent, TIP-(1-39) inhibited the actions of the three agonists with efficiencies similar to those of [Leu11,D-Trp12,Trp23,Tyr36] PTHrP-(7-36)amide, an established PTH1R antagonist. Taken together, the currently available data suggest that the carboxyl-terminal portion of TIP-(1-39) interacts efficiently with the PTH1R, at sites identical to or closely overlapping those used by PTH-(1-34) and PTHrP-(1-36). The amino-terminal residues of TIP-(1-39), however, are unable to interact productively with the PTH1R, thus enabling TIP-(1-39) and some of its truncated analogs to function as an antagonist at this receptor.

Original languageEnglish (US)
Pages (from-to)704-709
Number of pages6
JournalEndocrinology
Volume142
Issue number2
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Endocrinology

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