Genetic Deletion of p90 Ribosomal S6 Kinase 2 Alters Patterns of 5-Hydroxytryptamine2A 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 The American Society for Pharmacology and Experimental Therapeutics 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.
Cronan, Mark R.
Kroeze, Wesley K.
Sciaky, Noah
Roth, Bryan L.
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Title Genetic Deletion of p90 Ribosomal S6 Kinase 2 Alters Patterns of 5-Hydroxytryptamine2A Serotonin Receptor Functional Selectivity
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