TY - JOUR T1 - Genetic Deletion of p90 Ribosomal S6 Kinase 2 Alters Patterns of 5-Hydroxytryptamine<sub>2A</sub> Serotonin Receptor Functional Selectivity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 327 LP - 338 DO - 10.1124/mol.109.061440 VL - 77 IS - 3 AU - Ryan T. Strachan AU - Noah Sciaky AU - Mark R. Cronan AU - Wesley K. Kroeze AU - Bryan L. Roth Y1 - 2010/03/01 UR - http://molpharm.aspetjournals.org/content/77/3/327.abstract N2 - 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. It is noteworthy that functional selectivity accommodates significant changes in efficacy resulting from differential expression of G protein-coupled receptor modifying proteins (i.e., “conditional efficacy”)—a phenomenon with profound implications for drug discovery. We have uncovered a novel regulatory mechanism whereby p90 ribosomal S6 kinase 2 (RSK2) interacts with 5-hydroxytryptamine2A (5-HT2A) serotonin receptors and attenuates receptor signaling via direct receptor phosphorylation (Proc Natl Acad Sci U S A 103:4717–4722, 2006; J Biol Chem 284:5557–5573, 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 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.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics ER -