p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling.
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.
Sheffler
Douglas J
DJ
Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Kroeze
Wesley K
WK
Garcia
Bonnie G
BG
Deutch
Ariel Y
AY
Hufeisen
Sandra J
SJ
Leahy
Patrick
P
Brüning
Jens C
JC
Roth
Bryan L
BL
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D038921:Coffin-Lowry Syndrome / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists; D015398:Signal Transduction
D010716:Phosphatidylinositols; D044402:Receptor, Serotonin, 5-HT2A; D043562:Receptors, G-Protein-Coupled; D058826:Serotonin 5-HT2 Receptor Agonists; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3