The regulation of G protein-coupled receptor (GPCR) signal transduction byp90 ribosomal S6 kinase 2 (RSK2)

5-hydroxytryptamine 2A (5-HT2A) serotonin receptors are G-protein coupled receptors (GPCRs) that play prominent roles in both the central nervous system and in the periphery and are the site of action of many hallucinogens, antipsychotic drugs, and antidepressants. We have discovered that p90 Ribosomal S6 Kinase 2 (RSK2) interacts with 5-HT2A serotonin receptors in vitro and in vivo and modulates the signaling of 5HT2A and all tested G protein-coupled receptors (GPCRs). We initially evaluated 5-HT2A receptor signaling in fibroblasts obtained from RSK2 wild type (+/+) and knock-out (-/-) mice and found that 5-HT2A receptor-mediated phosphoinositide hydrolysis, calcium signaling, and both basal and 5-HT-stimulated p42/44 ERK phosphorylation were augmented in RSK2 -/- fibroblasts. Importantly, the increased basal p42/44 ERK phosphorylation was attenuated by a 5-HT2A receptor-selective antagonist, MDL100,907. Endogenous signaling to phosphoinositide hydrolysis by other GPCRs examined, including, P2Y-purinergic, PAR-1-thrombinergic and bradykinin-B receptors, was also potentiated in RSK2 -/- fibroblasts. We also found that beta1-adrenergic receptor signaling to adenlylate cyclase was augmented in RSK2 -/- fibroblasts. Re-introduction of wild type but not kinase-dead forms of RSK2 into RSK2 -/- fibroblasts reversed the phosphoinositide hydrolysis and calcium signaling phenotypes. Finally, the 5-HT2A receptor was determined to be phosphorylated by active RSK2. Intriguingly, inactivating mutations in RSK2 lead to Coffin-Lowry Syndrome, which is characterized by mental retardation, learning and coordination deficits, skeletal and craniofacial deformities, cardiovascular abnormalities, and psychosis. Together, these data indicate that RSK2 constitutively attenuates GPCR signaling and therefore alterations in GPCR signaling may account for many of the clinical manifestations of Coffin-Lowry Syndrome.