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 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.
Strachan
Ryan T
RT
Department of Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio, USA.
Sciaky
Noah
N
Cronan
Mark R
MR
Kroeze
Wesley K
WK
Roth
Bryan L
BL
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3