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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Garcia, Bonnie G. Hufeisen, Sandra J. Sheffler, Douglas J. Leahy, Patrick Roth, Bryan L. Brüning, Jens C. Deutch, Ariel Y. Kroeze, Wesley K. |
| Description | Author Affiliation: Sheffler DJ ( Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.); |
| Abstract | G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT)(2A) receptor signaling in fibroblasts obtained from RSK2 wild-type (+/+) and knockout (-/-) mice showed that 5-HT(2A) receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1/2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, beta1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2-/- fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a 'tonic brake' on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase/mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 12 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Coffin-Lowry Syndrome Genetics Receptors, G-Protein-Coupled Agonists Ribosomal Protein S6 Kinases, 90-kDa Metabolism Serotonin 5-HT2 Receptor Agonists Amino Acid Sequence Animals Cells, Cultured Fibroblasts Gene Deletion Hydrolysis Mice Mice, Knockout Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Molecular Sequence Data Phosphatidylinositols Phosphorylation Receptor, Serotonin, 5-HT2A Signal Transduction Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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