MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Richard, F.
Right arrow Articles by Kitabgi, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Richard, F.
Right arrow Articles by Kitabgi, P.

Vol. 60, Issue 6, 1392-1398, December 2001

Agonism, Inverse Agonism, and Neutral Antagonism at the Constitutively Active Human Neurotensin Receptor 2

Françoise Richard, Séverine Barroso, Jean Martinez, Catherine Labbé-Jullié, and Patrick Kitabgi

Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS) Unité Mixte Recherche 6097 Valbonne, France (F.R., S.B., P.K.); Faculté de Pharmacie, University of Montpellier, CNRS-Unité de Recherche Associée 1845, Montpellier, France (J.M.); and CNRS Unité Propre de Recherche et de l'Enseignement Supérieur-A 8068, Hôpital Cochin, Paris, France (C.L-J.)

Two G protein-coupled neurotensin (NT) receptors, termed NTR1 and NTR2, have been identified so far. In contrast to the NTR1, which has been extensively studied, little is known about the pharmacological and biological properties of the NTR2. In the course of characterizing NT analogs that exhibited binding selectivity for the NTR2, we discovered that this receptor constitutively activated inositol phosphate (IP) production. Here, we report on the constitutive activity of the human NTR2 (hNTR2) transfected in COS cells and on compounds that exhibit agonism, inverse agonism, and neutral antagonism at this receptor. IP levels increased linearly with time, whereas they remained constant in mock-transfected cells. Furthermore, IP production was proportional to the amount of hNTR2 present at the cell membrane. SR 48692, a nonpeptide antagonist of the NTR1, stimulated IP production, whereas levocabastine, a nonpeptide histamine H1 antagonist that binds the NTR2 but not the NTR1, behaved as a weak partial inverse agonist. NT analogs modified at position 11 of the NT molecule, in particular by the introduction of bulky aromatic D amino acids, exhibited binding selectivity at the hNTR2 and also behaved as partial inverse agonists, reversing constitutive IP production up to 50%. Finally, NT barely affected constitutive IP production but antagonized the effects of both agonist and inverse agonist compounds, thus behaving as a neutral antagonist. The unique pharmacological profile of the hNTR2 is discussed in the light of its sequence similarity with the NTR1 and the known binding site topology of NT and SR 48692 in the NTR1.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 EndocrinologyHome page
B. Holst, K. L. Egerod, E. Schild, S. P. Vickers, S. Cheetham, L.-O. Gerlach, L. Storjohann, C. E. Stidsen, R. Jones, A. G. Beck-Sickinger, et al.
GPR39 Signaling Is Stimulated by Zinc Ions But Not by Obestatin
Endocrinology, January 1, 2007; 148(1): 13 - 20.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
J H Li, F Sicard, M A Salam, M Baek, J LePrince, H Vaudry, K Kim, H B Kwon, and J Y Seong
Molecular cloning and functional characterization of a type-I neurotensin receptor (NTR) and a novel NTR from the bullfrog brain
J. Mol. Endocrinol., June 1, 2005; 34(3): 793 - 807.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Perron, P. Sarret, L. Gendron, T. Stroh, and A. Beaudet
Identification and Functional Characterization of a 5-Transmembrane Domain Variant Isoform of the NTS2 Neurotensin Receptor in Rat Central Nervous System
J. Biol. Chem., March 18, 2005; 280(11): 10219 - 10227.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Holst, N. D. Holliday, A. Bach, C. E. Elling, H. M. Cox, and T. W. Schwartz
Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family
J. Biol. Chem., December 17, 2004; 279(51): 53806 - 53817.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
L. Gendron, A. Perron, M. D. Payet, N. Gallo-Payet, P. Sarret, and A. Beaudet
Low-Affinity Neurotensin Receptor (NTS2) Signaling: Internalization-Dependent Activation of Extracellular Signal-Regulated Kinases 1/2
Mol. Pharmacol., December 1, 2004; 66(6): 1421 - 1430.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
T. Kenakin
Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism
Mol. Pharmacol., January 1, 2004; 65(1): 2 - 11.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
B. Holst, A. Cygankiewicz, T. H. Jensen, M. Ankersen, and T. W. Schwartz
High Constitutive Signaling of the Ghrelin Receptor--Identification of a Potent Inverse Agonist
Mol. Endocrinol., November 1, 2003; 17(11): 2201 - 2210.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics