Genetic deletion of p90 ribosomal S6 kinase 2 alters patterns of 5-hydroxytryptamine 2A serotonin receptor functional selectivity

• Published in: Molecular pharmacology Vol. 77; no. 3; pp. 327 - 338
• Main Authors: Strachan, Ryan T, Sciaky, Noah, Cronan, Mark R, Kroeze, Wesley K, Roth, Bryan L
• Format: Journal Article
• Language: English
• Published: United States 01.03.2010
• Subjects: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Gene Deletion; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mice, Knockout; Receptor, Serotonin, 5-HT2A - physiology; Ribosomal Protein S6 Kinases, 90-kDa - deficiency; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists - pharmacology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.109.061440

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-hydroxytryptamine(2A) (5-HT(2A)) 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-HT(2A) agonist signaling might be disproportionately affected by alterations in RSK2 expression. To test this hypothesis, we evaluated a chemically diverse set of 5-HT(2A) agonists at three readouts of 5-HT(2A) receptor activation in both wild-type (WT) and RSK2 knock-out (KO) mouse embryonic fibroblasts (MEFs). Here we report that 5-HT(2A) 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.