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

Molecular Pharmacology
Ryan T StrachanBryan L Roth

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 t...Continue Reading

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