@article {Strachanmol.109.061440, author = {Ryan T Strachan and Noah Sciaky and Mark R Cronan and Wesley K Kroeze and Bryan L Roth}, title = {Genetic deletion of p90 ribosomal S6 kinase 2 alters patterns of 5-HT2A serotonin receptor functional selectivity}, elocation-id = {mol.109.061440}, year = {2009}, doi = {10.1124/mol.109.061440}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The concept of functional selectivity has now thoroughly supplanted the previously entrenched notion of intrinsic efficacy by explaining how agonists and antagonists exhibit a range of efficacies for distinct receptor-mediated responses. Importantly, functional selectivity accommodates significant changes in efficacy resulting from differential expression of G protein-coupled receptor modifying proteins (i.e., {\textquoteright}conditional efficacy{\textquoteright})-a phenomenon with profound implications for drug discovery. Recently, we uncovered a novel regulatory mechanism whereby p90 ribosomal S6 kinase 2 (RSK2) interacts with 5-HT2A serotonin receptors and attenuates receptor signaling via direct receptor phosphorylation (Sheffler et al. PNAS 2006; Strachan et al. JBC 2009). This discovery, together with the mounting evidence for conditional efficacy, suggested to us that 5-HT2A agonist signaling might be disproportionately affected by alterations in RSK2 expression. To test this hypothesis, we evaluated a chemically diverse set of 5-HT2A agonists at three readouts of 5-HT2A receptor activation in both wild-type (WT) and RSK2 knock-out (KO) mouse embryonic fibroblasts (MEFs). Here we report that 5-HT2A receptor agonist efficacies were significantly and variably augmented in RSK2 KO MEFs when compared with WT MEFs. As a result, relative agonist efficacies were significantly altered, and even reversed, between WT and RSK2 KO MEFs for a single effector readout. This study provides the first evidence that deletion of a single kinase can elicit profound changes in patterns of agonist functional selectivity.The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2009/11/20/mol.109.061440}, eprint = {https://molpharm.aspetjournals.org/content/early/2009/11/20/mol.109.061440.full.pdf}, journal = {Molecular Pharmacology} }