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 Ambrosio, C.
Right arrow Articles by Costa, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ambrosio, C.
Right arrow Articles by Costa, T.

Vol. 57, Issue 1, 198-210, January 2000

Catechol-Binding Serines of beta 2-Adrenergic Receptors Control the Equilibrium between Active and Inactive Receptor States

Caterina Ambrosio, Paola Molinari, Susanna Cotecchia, and Tommaso Costa

Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy (C.A., P.M., T.C.); and the Institut de Pharmacologie et Toxicologie, Université de Lausanne, Faculté de Médecine, Lausanne, Switzerland (S.C.)

The binding free energy for the interaction between serines 204 and 207 of the fifth transmembrane helix of the beta 2-adrenergic receptor (beta 2-AR) and catecholic hydroxyl (OH) groups of adrenergic agonists was analyzed using double mutant cycles. Binding affinities for catecholic and noncatecholic agonists were measured in wild-type and mutant receptors, carrying alanine replacement of the two serines (S204A, S207A beta 2-AR), a constitutive activating mutation, or both. The free energy coupling between the losses of binding energy attributable to OH deletion from the ligand and from the receptor indicates a strong interaction (nonadditivity) as expected for a direct binding between the two sets of groups. However, we also measured a significant interaction between the deletion of OH groups from the receptor and the constitutive activating mutation. This suggests that a fraction of the decrease in agonist affinity caused by serine mutagenesis may involve a shift in the conformational equilibrium of the receptor toward the inactive state. Direct measurements using a transient transfection assay confirm this prediction. The constitutive activity of the (S204A, S207A) beta 2-AR mutant is 50 to 60% lower than that of the wild-type beta 2-AR. We conclude that S204 and S207 do not only provide a docking site for the agonist, but also control the equilibrium of the receptor between active (R*) and inactive (R) forms.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
R. A. Artigas, A. Gonzalez, E. Riquelme, C. A. Carvajal, A. Cattani, A. Martinez-Aguayo, A. M. Kalergis, T. Perez-Acle, and C. E. Fardella
A Novel Adrenocorticotropin Receptor Mutation Alters Its Structure and Function, Causing Familial Glucocorticoid Deficiency
J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 3097 - 3105.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. Kapur, D. P. Hurst, D. Fleischer, R. Whitnell, G. A. Thakur, A. Makriyannis, P. H. Reggio, and M. E. Abood
Mutation Studies of Ser7.39 and Ser2.60 in the Human CB1 Cannabinoid Receptor: Evidence for a Serine-Induced Bend in CB1 Transmembrane Helix 7
Mol. Pharmacol., June 1, 2007; 71(6): 1512 - 1524.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Ambrosio, P. Molinari, F. Fanelli, Y. Chuman, M. Sbraccia, O. Ugur, and T. Costa
Different Structural Requirements for the Constitutive and the Agonist-induced Activities of the {beta}2-Adrenergic Receptor
J. Biol. Chem., June 24, 2005; 280(25): 23464 - 23474.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. Del Carmine, P. Molinari, M. Sbraccia, C. Ambrosio, and T. Costa
"Induced-Fit" Mechanism for Catecholamine Binding to the {beta}2-Adrenergic Receptor
Mol. Pharmacol., August 1, 2004; 66(2): 356 - 363.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
D. P. Hurst, D. L. Lynch, J. Barnett-Norris, S. M. Hyatt, H. H. Seltzman, M. Zhong, Z.-H. Song, J. Nie, D. Lewis, and P. H. Reggio
N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) Interaction with LYS 3.28(192) Is Crucial for Its Inverse Agonism at the Cannabinoid CB1 Receptor
Mol. Pharmacol., December 1, 2002; 62(6): 1274 - 1287.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Claeysen, M. Sebben, C. Bécamel, R. M. Eglen, R. D. Clark, J. Bockaert, and A. Dumuis
Pharmacological Properties of 5-Hydroxytryptamine4 Receptor Antagonists on Constitutively Active Wild-Type and Mutated Receptors
Mol. Pharmacol., July 1, 2000; 58(1): 136 - 144.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
G. Liapakis, J. A. Ballesteros, S. Papachristou, W. C. Chan, X. Chen, and J. A. Javitch
The Forgotten Serine. A CRITICAL ROLE FOR Ser-2035.42 IN LIGAND BINDING TO AND ACTIVATION OF THE beta 2-ADRENERGIC RECEPTOR
J. Biol. Chem., November 22, 2000; 275(48): 37779 - 37788.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Marie, E. Richard, D. Pruneau, J.-L. Paquet, C. Siatka, R. Larguier, C. Ponce, P. Vassault, T. Groblewski, B. Maigret, et al.
Control of Conformational Equilibria in the Human B2 Bradykinin Receptor. MODELING OF NONPEPTIDIC LIGAND ACTION AND COMPARISON TO THE RHODOPSIN STRUCTURE
J. Biol. Chem., October 26, 2001; 276(44): 41100 - 41111.
[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 © 2000 by the American Society for Pharmacology and Experimental Therapeutics