@article {Baker986, author = {Jillian G. Baker and Ian P. Hall and Stephen J. Hill}, title = {Temporal Characteristics of cAMP Response Element-Mediated Gene Transcription: Requirement for Sustained cAMP Production}, volume = {65}, number = {4}, pages = {986--998}, year = {2004}, doi = {10.1124/mol.65.4.986}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 β antagonists do stimulate very small β2 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 β2 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 {\textquotedblleft}β-blockers{\textquotedblright}) may cause more substantial gene transcription than previously believed.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/65/4/986}, eprint = {https://molpharm.aspetjournals.org/content/65/4/986.full.pdf}, journal = {Molecular Pharmacology} }