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

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 sign...

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Published inMolecular 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
LanguageEnglish
Published United States 01.03.2010
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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. 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.
AbstractList 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.
Author Strachan, Ryan T
Kroeze, Wesley K
Roth, Bryan L
Sciaky, Noah
Cronan, Mark R
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Snippet The concept of functional selectivity has now thoroughly supplanted the previously entrenched notion of intrinsic efficacy by explaining how agonists and...
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StartPage 327
SubjectTerms 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
Title Genetic deletion of p90 ribosomal S6 kinase 2 alters patterns of 5-hydroxytryptamine 2A serotonin receptor functional selectivity
URI https://www.ncbi.nlm.nih.gov/pubmed/19933401
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