Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms underlying desensitization of serotonin 2A (5-HT(2A)) receptor signaling by antagonists are unclear but may involve changes in gene expression mediated via signal transduction pathways. In cells in culture, olanzapine causes desensitization of 5-HT(2A) receptor signaling and increases the levels of regulators of G protein signaling (RGS) 7 protein dependent on phosphorylation/activation of the Janus kinase 2 (Jak2)/signal transducers and activators of transcription 3 (Stat3) signaling pathway. In the current study, the 5-HT(2A) receptor signaling system in rat frontal cortex was examined following 7 days of daily treatment with 0.5, 2.0 or 10.0 mg/kg i.p. olanzapine. Olanzapine increased phosphorylation of Stat3 in rats treated daily with 10 mg/kg olanzapine and caused a dose-dependent desensitization of 5-HT(2A) receptor-mediated phospholipase C activity. There were dose-dependent increases in the levels of membrane-associated 5-HT(2A) receptor, G(alpha11) and G(alphaq) protein levels but no changes in the G(beta) protein levels. With olanzapine treatment, RGS4 protein levels increase in the membrane-fraction and decrease in the cytosolic fraction by similar amounts suggesting a redistribution of RGS4 protein within neurons. RGS7 protein levels increase in both the membrane and cytosolic fractions in rats treated daily with 10mg/kg olanzapine. The olanzapine-induced increase in Stat3 activity could underlie the increase in RGS7 protein expression in vivo as previously demonstrated in cultured cells. Furthermore, the increases in membrane-associated RGS proteins could play a role in desensitization of signaling by terminating the activated G(alphaq/11) proteins more rapidly.
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PMID:Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex. 1767 5

Regulator of G-protein signaling (RGS) 4 negatively modulates signaling of several Galpha(q)-coupled receptors, including metabotropic glutamate receptor (mGluR) subtype 5 in neuronal and non-neuronal cell lines. In the brain, both RGS4 and mGluR5 receptors are enriched in the striatum, and their functions have been linked to psychostimulant-induced behavior and synaptic plasticity. However, it is not known whether RGS4 and mGluR5 interactions occur in rat striatum and whether chronic amphetamine (AMPH) treatment produces changes in RGS4 levels that are correlated with mGluR5 receptor activity. Using coimmunoprecipitation, the present study demonstrated that endogenous RGS4 binds mGluR5 receptors as well as key mGluR5-associated proteins, Galpha(q/11), and phospholipase C-beta1 (PLCbeta1) in preparations from rat striatum. In the next experiment, rats were treated with AMPH (5 mg/kg i.p. daily) for 5 days followed by 3 weeks of abstinence. At this time point, animals pretreated with AMPH displayed sensitized behavioral responses to AMPH challenge and decreased RGS4 protein in dorsal striatum and nucleus accumbens. Behavioral sensitization to AMPH was also accompanied by an increase in Galpha(q/11) and PLCbeta1 in dorsal striatum. In contrast, total levels of mGluR5 receptors in the striatum were not altered by any AMPH treatment. In conclusion, the present study demonstrates that RGS4 protein is an integral part of the mGluR5 protein complex in the striatum. This study further suggests that AMPH-induced changes in mGluR5-associated protein levels (RGS4, Galpha(q/11), and PLCbeta1) may be related to altered coupling of striatal mGluR5 receptors in animals sensitized to AMPH.
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PMID:Regulator of G-protein signaling 4 interacts with metabotropic glutamate receptor subtype 5 in rat striatum: relevance to amphetamine behavioral sensitization. 1769 84