![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication May 16, 2006.
Revised August 9, 2006.
Accepted for publication August 10, 2006.
1 and 2 Adrenergic Receptor Ligands towards Adenylyl Cyclase and Mitogen-Activated Protein Kinase Reveals the Pluridimensionality of Efficacy
Drug efficacy is classically considered an intrinsic property of a ligand/receptor couple. However, recent observations suggest that efficacy may also be influenced by the signaling effectors engaged by a unique receptor. To directly and systematically test this possibility, we assessed the ability of a panel of 
-adrenergic ligands to modulate the activity of two effector systems, the adenylyl cyclase (AC) and the mitogen-activated protein kinase (MAPK) via 1 and 2 adrenergic receptors. Although some compounds displayed similar efficacies toward the two pathways, others showed complex efficacy profiles. For example, compounds that are inverse agonists for the AC activity were found to be either agonists, neutral antagonists or inverse agonists for the MAPK pathway. Reciprocally, agonists for the AC were either agonists or neutral antagonists for MAPK. Given this complexity, we propose a Cartesian representation of the efficacies that takes into account the activities of the different effectors that can be engaged by a given receptor. In addition, compounds considered as non-selective for 1 and 2 adrenergic receptors, based on their binding affinities, showed distinct relative efficacy profiles toward AC and MAPK, adding a new dimension to the concept of ligand selectivity. Taken together, the results suggest that binding of different ligands promote distinct conformational changes leading to specific signaling outcomes. Our data therefore clearly illustrate that efficacy is a pluridimensional parameter that is not an intrinsic characteristic of a ligand/receptor couple. This should have important implications for the future design of screening assays used in drug discovery campaigns.
Key words:
Adrenergic, Adenylyl cyclases, cAMP, MAP Kinase
This article has been cited by other articles:
|
|
 |
|
  M. Sato, D. S. Hutchinson, B. A. Evans, and R. J. Summers Mol. Pharmacol., November 1, 2008; 74(5): 1417 - 1428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I.-M. Kim, D. G. Tilley, J. Chen, N. C. Salazar, E. J. Whalen, J. D. Violin, and H. A. Rockman {beta}-Blockers alprenolol and carvedilol stimulate {beta}-arrestin-mediated EGFR transactivation PNAS, September 23, 2008; 105(38): 14555 - 14560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Galandrin, G. Oligny-Longpre, H. Bonin, K. Ogawa, C. Gales, and M. Bouvier Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased Mitogen-Activated Protein Kinase Signaling through the {beta}1-Adrenergic Receptor Mol. Pharmacol., July 1, 2008; 74(1): 162 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Lin, B. Zhu, W. Zhang, H. Dang, B.-X. Zhang, M. S. Katz, and C.-K. Yeh Distinct pathways of ERK activation by the muscarinic agonists pilocarpine and carbachol in a human salivary cell line Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1454 - C1464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Cordeaux, S. J. Briddon, S. P. H. Alexander, B. Kellam, and S. J. Hill Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells FASEB J, March 1, 2008; 22(3): 850 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Drake, J. D. Violin, E. J. Whalen, J. W. Wisler, S. K. Shenoy, and R. J. Lefkowitz {beta}-Arrestin-biased Agonism at the {beta}2-Adrenergic Receptor J. Biol. Chem., February 29, 2008; 283(9): 5669 - 5676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kenakin Functional Selectivity through Protean and Biased Agonism: Who Steers the Ship? Mol. Pharmacol., December 1, 2007; 72(6): 1393 - 1401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sato, T. Horinouchi, D. S. Hutchinson, B. A. Evans, and R. J. Summers Ligand-Directed Signaling at the beta3-Adrenoceptor Produced by 3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) Relative to Receptor Agonists Mol. Pharmacol., November 1, 2007; 72(5): 1359 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Wisler, S. M. DeWire, E. J. Whalen, J. D. Violin, M. T. Drake, S. Ahn, S. K. Shenoy, and R. J. Lefkowitz A unique mechanism of beta-blocker action: Carvedilol stimulates beta-arrestin signaling PNAS, October 16, 2007; 104(42): 16657 - 16662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Tutor, P. Penela, and F. Mayor Jr. Anti-{beta}1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells Cardiovasc Res, October 1, 2007; 76(1): 51 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Lane, B. Powney, A. Wise, S. Rees, and G. Milligan Protean Agonism at the Dopamine D2 Receptor: (S)-3-(3-Hydroxyphenyl)-N-propylpiperidine Is an Agonist for Activation of Go1 but an Antagonist/Inverse Agonist for Gi1,Gi2, and Gi3 Mol. Pharmacol., May 1, 2007; 71(5): 1349 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Neubig Missing Links: Mechanisms of Protean Agonism Mol. Pharmacol., May 1, 2007; 71(5): 1200 - 1202. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
