MolPharm xPharm- The Comprehensive Pharmacology Reference

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 Wade, S. M.
Right arrow Articles by Neubig, R. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wade, S. M.
Right arrow Articles by Neubig, R. R.

Vol. 59, Issue 3, 532-542, March 2001

Inverse Agonist Activity at the alpha 2A-Adrenergic Receptor

Susan M. Wade, Keng-Li Lan, Dorian J. Moore, and Richard R. Neubig

Departments of Pharmacology (S.M.W., K-L.L., D.J.M., R.R.N.) and Internal Medicine/Hypertension (R.R.N.), The University of Michigan, Ann Arbor, Michigan

Constitutive activation of G protein-coupled receptors (GPCRs) is now well recognized and many classical GPCR antagonists have been found to be inverse agonists. For the alpha 2A-adrenergic receptor (AR) we determine the relative inverse efficacies of a series of antagonists and utilize the extended ternary complex model to estimate the fraction of constitutively active mutant (CAM) receptors in the active state. Stable Chinese hamster ovary cell lines expressing the porcine alpha 2A-AR in its wild-type (WT) and constitutively activated (CAM-T373K) form were isolated. Activation of both Gi and Gs was enhanced for CAM receptors. cAMP production was suppressed in cells with the CAM alpha 2A-AR and this suppression was reversed by alpha 2-adrenergic antagonists with an order of inverse efficacy of rauwolscine > yohimbine > RX821002 > MK912, whereas phentolamine and idazoxan were essentially neutral antagonists. This striking difference in inverse efficacy between idazoxan and RX821002 may account for in vivo pharmacological differences between these two alpha 2-adrenergic antagonists. Agonist binding affinity to the non-G protein-coupled CAM receptor was 3- to 9-fold higher than to WT, whereas binding of the most efficacious inverse agonists, yohimbine and rauwolscine, was 1.7- and 2.1-fold weaker. Analysis of this difference by the extended ternary complex model indicates that approximately 50% of the CAM alpha 2A-AR is in the active (R*) state although there is no detectable constitutive activity of the WT receptor in the absence of agonist.

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


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
A. Kapur, P. Samaniego, G. A. Thakur, A. Makriyannis, and M. E. Abood
Mapping the Structural Requirements in the CB1 Cannabinoid Receptor Transmembrane Helix II for Signal Transduction
J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 341 - 348.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. R. Dowling, J. M. Willets, D. C. Budd, S. J. Charlton, S. R. Nahorski, and R. A. J. Challiss
A Single Point Mutation (N514Y) in the Human M3 Muscarinic Acetylcholine Receptor Reveals Differences in the Properties of Antagonists: Evidence for Differential Inverse Agonism
J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1134 - 1142.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. P. Nelson, S. R. Nahorski, and R. A. J. Challiss
Constitutive Activity and Inverse Agonism at the M2 Muscarinic Acetylcholine Receptor
J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 279 - 288.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. P. Fitzsimons, F. Monczor, N. Fernandez, C. Shayo, and C. Davio
Mepyramine, a Histamine H1 Receptor Inverse Agonist, Binds Preferentially to a G Protein-coupled Form of the Receptor and Sequesters G Protein
J. Biol. Chem., August 13, 2004; 279(33): 34431 - 34439.
[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
 J. Pharmacol. Exp. Ther.Home page
K. Takahashi, S. Tokita, and H. Kotani
Generation and Characterization of Highly Constitutive Active Histamine H3 Receptors
J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 213 - 218.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
P. J. Pauwels, I. Rauly, and T. Wurch
Dissimilar Pharmacological Responses by a New Series of Imidazoline Derivatives at Precoupled and Ligand-Activated {alpha}2A-Adrenoceptor States: Evidence for Effector Pathway-Dependent Differential Antagonism
J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1015 - 1023.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
R.-P. Xiao
{beta}-Adrenergic Signaling in the Heart: Dual Coupling of the {beta}2-Adrenergic Receptor to Gs and Gi Proteins
Sci. Signal., October 16, 2001; 2001(104): re15 - re15.
[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