期刊
MOLECULAR PHARMACOLOGY
卷 77, 期 3, 页码 327-338出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.109.061440
关键词
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资金
- National Institutes of Health National Institute of Mental Health Psychoactive Drug Screening Program [R01-MH61887, U19-MH82441]
- Michael Hooker Chair for Therapeutics and Translational Proteomics
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-HT2A) 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-HT2A agonist signaling might be disproportionately affected by alterations in RSK2 expression. To test this hypothesis, we evaluated a chemically diverse set of 5-HT2A agonists at three readouts of 5-HT2A receptor activation in both wild-type (WT) and RSK2 knockout (KO) mouse embryonic fibroblasts (MEFs). Here we report that 5-HT2A 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.
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