Inverse agonism of amino-terminally truncated parathyroid hormone (PTH) and PTH-related peptide (PTHrP) analogs revealed with constitutively active mutant PTH/PTHrP receptors

Inverse agonists, ligands that suppress spontaneous receptor signaling activity, have been described for a growing number of G protein-coupled receptors; however, none have been reported for the PTH/calcitonin/secretin receptor family. We took advantage of the constitutive signaling activity of two...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 1996-09, Vol.137 (9), p.3936-3941
Main Authors: Gardella, T J, Luck, M D, Jensen, G S, Schipani, E, Potts, J T, Jüppner, H
Format: Article
Language:English
Subjects:
Analogs
Calcitonin
Chondrodystrophy
G protein-coupled receptors
Inverse agonists
Ligands
Mutants
Parathyroid hormone
Parathyroid hormone-related protein
Parathyroid hormone-related protein receptors
Peptides
Proteins
Receptors
Secretin
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Summary:Inverse agonists, ligands that suppress spontaneous receptor signaling activity, have been described for a growing number of G protein-coupled receptors; however, none have been reported for the PTH/calcitonin/secretin receptor family. We took advantage of the constitutive signaling activity of two mutant forms of the PTH/PTH-related peptide (PTHrP) receptor, recently identified in patients with Jansen's metaphyseal chondrodysplasia, to screen for PTH and PTHrP analogs with inverse agonist activity. Two antagonist peptides, [Leu11, D-Trp12]hPTHrP(7-34)NH2 and [D-Trp12, Tyr34]bPTH-(7-34)NH2, displayed inverse agonist activity and reduced cAMP in COS-7 cells expressing either mutant receptor by 30-50% (EC50 approximately 50 nM). These data demonstrate that the concept of inverse agonism can be extended to this distinct family of G protein-coupled receptors and their cognate antagonist peptide ligands. Such ligands shall be useful probes of the multi-state conformational equilibria proposed for these receptors and could lead to new approaches for treating human diseases caused by receptor activating mutations.
ISSN:0013-7227
1945-7170
DOI:10.1210/endo.137.9.8756569