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Protein kinase C? activity regulates mGluR5 surface expression in the rat nucleus accumbens.

ABSTRACT: Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to G?q/11 protein signaling. We have previously demonstrated that the epsilon isoform of PKC (PKC?) is a critical downstream target of mGluR5 in regulating behavioral and biochemical responses to alcohol. Recent evidence suggests that PKC-mediated phosphorylation of mGluR5 can lead to receptor desensitization and internalization. We therefore sought to examine the specific involvement of PKC? in the regulation of mGluR5 surface expression in the nucleus accumbens (NAc), a key regulator of alcohol-associated behaviors. Coronal brain sections from male Wistar rats were analyzed for either colocalization of mGluR5 and PKC? via immunohistochemistry or changes in mGluR5 surface expression and PKC? phosphorylation following local application of PKC? translocation activator or inhibitor peptides and/or an orthosteric mGluR5 agonist. We observed colocalization of mGluR5 and PKC? in the NAc. We also showed that intra-NAc infusion of the PKC? translocation inhibitor ?V1-2 increased mGluR5 surface expression under baseline conditions. Stimulation of mGluR5 with an orthosteric agonist DHPG, dose dependently increased ERK1/2 and PKC? phosphorylation as well as mGluR5 internalization in acute NAc slices. Finally, we observed that activation of PKC? translocation with Tat-??RACK peptide mediates agonist-independent mGluR5 internalization, whereas PKC? translocation inhibitor ?V1-2 prevents agonist-dependent internalization of mGluR5 in NAc slice preparations. These findings suggest that the subcellular localization of mGluR5 in the NAc is regulated by PKC? under basal and stimulation conditions, which may influence the role of mGluR5-PKC? signaling in alcohol-related behaviors. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Schwendt M

PROVIDER: S-EPMC5296288 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Protein kinase Cɛ activity regulates mGluR5 surface expression in the rat nucleus accumbens.

Schwendt Marek M Olive M Foster MF

Journal of neuroscience research 20160821 4

Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to G<sub>αq/11</sub> protein signaling. We have previously demonstrated that the epsilon isoform of PKC (PKCɛ) is a critical downstream target of mGluR5 in regulating behavioral and biochemical responses to alcohol. Recent evidence suggests that PKC-mediated phosphorylation of mGluR5 can lead to receptor desensitization and internalization. We therefore sought to examine the specific involvement of PKCɛ ...[more]

PMID: 27546836

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Project description:Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA), both performed using protein quantitative data, demonstrate that cocaine increases vesicular transporters for dopamine and glutamate as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins implicated in a diverse number of neuronal functions (e.g., energy production, mRNA splicing, and ubiquitination), molecular cascades (e.g., protein kinases), psychiatric disorders (e.g., mood disorders), and neurodegenerative diseases (e.g., Huntington's and Alzheimer's diseases). Upregulation of energy metabolism components in EC rats was verified using RNA sequencing. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics. Proteomics data are available via ProteomeXchange with identifier PXD000990.

Dataset Information

Protein kinase C? activity regulates mGluR5 surface expression in the rat nucleus accumbens.

Publications

Protein kinase Cɛ activity regulates mGluR5 surface expression in the rat nucleus accumbens.

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