QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

Temporal Characteristics of cAMP Response Element-Mediated Gene Transcription: Requirement for Sustained cAMP Production

Institute of Cell Signalling, Medical School, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom

Many clinically used drugs are G-protein-coupled receptor (GPCR) antagonists and are given long-term to prevent receptor activation by endogenous agonists. Most GPCR antagonists are considered to have little agonist efficacy of their own. However, many antagonists do stimulate very small ₂ adrenoceptor-mediated cAMP responses, but these responses become substantial at the level of cAMP response element (CRE)-gene transcription. Here, we compared the temporal characteristics of these ₂ adrenoceptor-mediated cAMP and CRE-gene transcription responses with ligands of differing agonist efficacy. Within a minute, full agonists (e.g., isoprenaline) stimulated large increases in intracellular and exported cAMP. Very weak partial agonists (e.g., alprenolol) did not increase intracellular cAMP (only stimulating a small export). However, all agonists (regardless of efficacy) stimulated an increase in CRE-gene transcription after a 2-h incubation. An initial 30-min continual stimulation was required to initiate the process of CRE-gene transcription for all ligands. Longer agonist incubations resulted in larger gene transcription responses in a proportional manner for both weak and full agonists alike, and this was despite the lack of intracellular cAMP detection for the weaker ligands. Thus, the major initiator for CRE-gene transcription was not cAMP concentration or total quantity generated but a sustained turnover of intracellular cAMP and hence sustained stimulation of CREB phosphorylation. Thus, long-acting agonists and long-term treatments with very weak partial agonists (including many drugs classified previously as antagonists based on traditional second-messenger assays, e.g., several clinically used "-blockers") may cause more substantial gene transcription than previously believed.

Address correspondence to: Prof. S. J. Hill, Institute of Cell Signaling, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. E-Mail: stephen.hill{at}nottingham.ac.uk

This article has been cited by other articles:

				P. Mardones, J. F. Medina, and R. P. J. O. Elferink Activation of Cyclic AMP Signaling in Ae2-deficient Mouse Fibroblasts J. Biol. Chem., May 2, 2008; 283(18): 12146 - 12153. [Abstract] [Full Text] [PDF]

				J. G. Baker and S. J. Hill A Comparison of the Antagonist Affinities for the Gi- and Gs-Coupled States of the Human Adenosine A1-Receptor J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 218 - 228. [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]

				I. H. Heijink, E. Vellenga, J. Oostendorp, J. G. R. de Monchy, D. S. Postma, and H. F. Kauffman Exposure to TARC alters {beta}2-adrenergic receptor signaling in human peripheral blood T lymphocytes Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L53 - L59. [Abstract] [Full Text] [PDF]