![[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}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
-Blockers at the Human 2-Adrenoceptor Provide Evidence for Agonist-Directed Signaling
Institute of Cell Signalling, Medical School, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom
-Blockers have beneficial effects in heart failure, although the underlying mechanism is unknown. 2-Adrenoceptors, however, are proportionally higher in the failing human heart. This study shows several clinically used -blockers are agonists at the human 2-adrenoceptor. Although these agonist effects were small at the cAMP level, they were substantial at the level of cAMP response element (CRE)-mediated gene transcription. Some of the effects of "-blockers" seen in heart failure may be related to the 2-agonist actions of these compounds. CRE-gene transcription responses to 2-agonists, forskolin, and cAMP-analogs were sensitive to p42/44-mitogen-activated protein (MAP) kinase pathway inhibitors. p42/44-MAP kinase activation was also shown directly by western blotting and enzyme-linked immunosorbent assay techniques. N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89; a protein kinase A inhibitor) stimulated cAMP accumulation and CRE gene transcription via the 2-adrenoceptor at concentrations at which protein kinase A was inhibited, providing evidence for an alternative pathway. Propranolol, however, produced paradoxical effects; it reduced basal cAMP accumulation (via 2-mediated inverse agonism) but stimulated 2-mediated CRE gene transcription. This cannot be explained by a sequential pathway from Gs-adenylyl cyclase-cAMP to CRE binding protein phosphorylation. Both responses to propranolol were insensitive to pertussis toxin, thus excluding Gi-protein involvement. Propranolol CRE gene transcription responses were attenuated by p42/44-MAP kinase inhibitors and propranolol was also found to directly stimulate the p42/44-MAP kinase pathway. Studies of inositol phosphate accumulation and of protein kinase C or Rho kinase inhibitors on CRE-gene transcription provided no evidence for Gq/11 or G12/13 involvement. These data suggest that propranolol can simultaneously act as an inverse agonist through a Gs-coupled mechanism while stimulating the p42/44-MAP kinase pathway through an alternative G-protein-independent mechanism.
Address correspondence to: Professor S. J. Hill, Institute of Cell Signaling, Queen's Medical Centre, Nottingham NG7 2UH, UK. E-mail: stephen.hill{at}nottingham.ac.uk
This article has been cited by other articles:
|
|
 |
|
  D. Wenzel, R. Knies, M. Matthey, A. M. Klein, J. Welschoff, V. Stolle, P. Sasse, W. Roll, J. Breuer, and B. K. Fleischmann {beta}2-Adrenoceptor Antagonist ICI 118,551 Decreases Pulmonary Vascular Tone in Mice via a Gi/o Protein/Nitric Oxide-Coupled Pathway Hypertension, July 1, 2009; 54(1): 157 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Schroder, N. Merten, J. M. Mathiesen, L. Martini, A. Kruljac-Letunic, F. Krop, A. Blaukat, Y. Fang, E. Tran, T. Ulven, et al. The C-terminal Tail of CRTH2 Is a Key Molecular Determinant That Constrains G{alpha}i and Downstream Signaling Cascade Activation J. Biol. Chem., January 9, 2009; 284(2): 1324 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
S. Galandrin and M. Bouvier Distinct Signaling Profiles of beta1 and beta2 Adrenergic Receptor Ligands toward Adenylyl Cyclase and Mitogen-Activated Protein Kinase Reveals the Pluridimensionality of Efficacy Mol. Pharmacol., November 1, 2006; 70(5): 1575 - 1584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Shenoy, M. T. Drake, C. D. Nelson, D. A. Houtz, K. Xiao, S. Madabushi, E. Reiter, R. T. Premont, O. Lichtarge, and R. J. Lefkowitz beta-Arrestin-dependent, G Protein-independent ERK1/2 Activation by the beta2 Adrenergic Receptor J. Biol. Chem., January 13, 2006; 281(2): 1261 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Baker Evidence for a Secondary State of the Human {beta}3-Adrenoceptor Mol. Pharmacol., December 1, 2005; 68(6): 1645 - 1655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Carter and S. J. Hill Characterization of Isoprenaline- and Salmeterol-Stimulated Interactions between {beta}2-Adrenoceptors and {beta}-Arrestin 2 Using {beta}-Galactosidase Complementation in C2C12 Cells J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 839 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Mathiesen, T. Ulven, L. Martini, L. O. Gerlach, A. Heinemann, and E. Kostenis Identification of Indole Derivatives Exclusively Interfering with a G Protein-Independent Signaling Pathway of the Prostaglandin D2 Receptor CRTH2 Mol. Pharmacol., August 1, 2005; 68(2): 393 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Hellstrand, E A Danielsen, V M Steen, A Ekman, E Eriksson, and C L Nilsson The ser9gly SNP in the dopamine D3 receptor causes a shift from cAMP related to PGE2 related signal transduction mechanisms in transfected CHO cells J. Med. Genet., November 1, 2004; 41(11): 867 - 871. [Full Text] [PDF]
|
|
|
|
|
|
J. G. Baker, I. P. Hall, and S. J. Hill Temporal Characteristics of cAMP Response Element-Mediated Gene Transcription: Requirement for Sustained cAMP Production Mol. Pharmacol., April 1, 2004; 65(4): 986 - 998. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
