Selective and nonselective inverse agonists for constitutively active type-1 parathyroid hormone receptors

Evidence for altered receptor conformations

P. H. Carter, B. D. Petroni, R. C. Gensure, E. Schipani, Jr Potts J.T., T. J. Gardella

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The spontaneous signaling activity of some G protein-coupled receptors and the capacity of certain ligands (inverse agonists) to inhibit such constitutive activity are poorly understood phenomena. We investigated these processes for several analogs of PTH-related peptide (PTHrP) and the constitutively active human PTH/PTHrP receptors (hP1Rcs) hP1Rc-H223R and hP1Rc-T410P. The N-terminally truncated antagonist PTHrP(5-36) functioned as a weak partial/neutral agonist with both mutant receptors but was converted to an inverse agonist for both receptors by the combined substitution of Leu11 and D-Trp12. The N-terminally intact analog [Bpa2]PTHrP(1-36) - a partial agonist with the wild-type hP1Rc - was a selective inverse agonist, in that it depressed basal cAMP signaling by hP1Rc-H223R but enhanced signaling by hP1Rc-T410P. The ability of [Bpa2] PTHrP(1-36) to discriminate between the two receptor mutants suggested that H223R and T410P confer constitutive receptor activity by inducing distinct conformational changes. This hypothesis was confirmed by the observations that: 1) the double mutant receptor hP1Rc-H223R/T410P exhibited basal cAMP levels that were 2-fold higher than those of either single mutant; and 2) hP1Rc-H223R and hP1Rc-T410P internalized 125I-PTHrP(5-36) to markedly different extents. The overall results thus reveal that two different types of inverse agonists are possible for PTHrP ligands (nonselective and selective) and that constitutively active PTH-1 receptors can access different conformational states.

Original languageEnglish (US)
Pages (from-to)1534-1545
Number of pages12
JournalEndocrinology
Volume142
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

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Parathyroid Hormone Receptor Type 1
Parathyroid Hormone-Related Protein
Ligands
G-Protein-Coupled Receptors

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Selective and nonselective inverse agonists for constitutively active type-1 parathyroid hormone receptors : Evidence for altered receptor conformations. / Carter, P. H.; Petroni, B. D.; Gensure, R. C.; Schipani, E.; Potts J.T., Jr; Gardella, T. J.

In: Endocrinology, Vol. 142, No. 4, 2001, p. 1534-1545.

Research output: Contribution to journalArticle

Carter, P. H. ; Petroni, B. D. ; Gensure, R. C. ; Schipani, E. ; Potts J.T., Jr ; Gardella, T. J. / Selective and nonselective inverse agonists for constitutively active type-1 parathyroid hormone receptors : Evidence for altered receptor conformations. In: Endocrinology. 2001 ; Vol. 142, No. 4. pp. 1534-1545.
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