Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice

Blasio, Angelo; Wang, Jingyi; Wang, Dan; Varodayan, Florence P.; Pomrenze, Matthew B.; Miller, Jacklyn; Lee, AM; McMahon, Thomas; Gyawali, Sandeep; Wang, Hua Yu; Roberto, Marisa; McHardy, Stanton F.; Pleiss, Michael A.; Messing, Robert O.

doi:10.1016/j.biopsych.2017.10.017

Cited by 22 publications

(28 citation statements)

References 30 publications

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“…Our results not only highlight the relevance of PKCα in the control of the transcriptional regulation of genes relative to the nPKCs in lung cancer cells, but also unveil the intricacies in the biological patterns controlled by the DAG pathway. Due to the widespread implications of phorbol ester/DAG receptors in cancer, neurological and cardiovascular disorders 3,62–64 , the generation of C1 domain ligands with distinctive specificity may represent promising therapeutic leads and pharmacological tools for dissecting the pathophysiological basis of disease.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Cooke

Casado‐Medrano

Ann

et al. 2019

Sci Rep

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Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation of PKC isozyme-specific modulators acting via the C1 domain, the binding site for the lipid second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. Synthetic efforts had recently led to the identification of AJH-836, a DAG-lactone with preferential affinity for novel isozymes (nPKCs) relative to classical PKCs (cPKCs). Here, we compared the ability of AJH-836 and a prototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to induce changes in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereas AJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1 , MMP9 , and MMP10 were among the genes most prominently induced by PMA, an effect impaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive gene signature analysis and bioinformatics efforts, including functional enrichment and transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differential involvement of individual PKC isozymes in the control of gene expression, our studies emphasize the importance of generating targeted C1 domain ligands capable of differentially regulating PKC isozyme-specific function in cellular models.

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Section: Discussionmentioning

confidence: 99%

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Cooke

Casado‐Medrano

Ann

et al. 2019

Sci Rep

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“…Exogenous application of CRF to CeA slices increases presynaptic GABA release in a CRF1, but not CRF2, -dependent manner (Kang-Park et al , 2015; Nie et al , 2004; Roberto et al , 2010). The effects of CRF on inhibitory neurotransmission in the CeA are regulated in part by protein kinase C-epsilon (PKCε); PKCε knockout mice exhibited increased baseline GABAergic tone in the CeA but were not responsive to the acute effects of exogenous CRF application, and PKCε inhibition occluded the effects of acute CRF in wild type mice (Bajo et al , 2008; Blasio et al , 2017). CRF has also been shown to alter excitatory transmission within the CeA.…”

Section: Crf and Amygdala Microcircuitrymentioning

confidence: 99%

“…Binge-like alcohol drinking, in which non-dependent subjects achieve a high blood-alcohol concentration during a limited window of alcohol access, has been shown to increase expression of PKCε in the CeA, and inhibition of PKCε specifically within the CeA reduced alcohol consumption in the binge model (Cozzoli et al , 2016). Given that PKCε has been shown to mediate some of the effects of CRF and alcohol on CeA GABAergic activity (Bajo et al , 2008; Blasio et al , 2017), the relationship between PKCε, CRF1 signaling and alcohol consumption warrants further investigation. If indeed native PKCε serves to inhibit GABAergic activity in the CeA, the acute increase in PKCε expression following sub-chronic alcohol exposure may represent a compensatory mechanism to offset the acute enhancement of GABAergic signaling induced by alcohol.…”

Section: The Crf System Fear and Alcohol In The Amygdalamentioning

confidence: 99%

The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry

Agoglia

Herman

2018

Alcohol

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The commonalities between different phases of stress and alcohol use as well as the high comorbidity between alcohol use disorders (AUDs) and anxiety disorders suggest common underlying cellular mechanisms governing the rewarding and aversive aspects of these related conditions. As an integrative center that assigns emotional salience to a wide variety of internal and external stimuli, the amygdala complex plays a major role in how alcohol and stress influence cellular physiology to produce disordered behavior. Previous work has illustrated the broad role of the amygdala in alcohol, stress, and anxiety. However, the challenge of current and future studies is to identify the specific dysregulations that occur within distinct amygdala circuits and subpopulations and the commonalities between these alterations in each disorder, with the long-term goal of identifying potential targets for therapeutic intervention. Specific intra-amygdala circuits and cell type-specific subpopulations are emerging as critical targets for stress- and alcohol-induced plasticity, chief among them the corticotropin releasing factor (CRF) and CRF receptor 1 (CRF1) system. CRF and CRF1 have been implicated in the effects of alcohol in several amygdala nuclei, including the basolateral (BLA) and central amygdala (CeA); however, the precise circuitry involved in these effects and the role of these circuits in stress and anxiety are only beginning to be understood.

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“…Given evidence for the role of PKCε in AUD, a recent study tested several novel molecules that act as PKCε inhibitors. They found that two compounds inhibited PKCε with Ki <20 nM, were highly selective of PKCε, crossed the bloodbrain barrier, prevented alcohol-stimulated GABA release in the central amygdala, and reduced alcohol consumption in an intermittent 24-hour access, two-bottle choice drinking paradigm in wild-type but not in Prkce -/mice (18).…”

Section: Promising Molecular Targetsmentioning

confidence: 99%

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

Gray

Murphy

Leggio

2019

Preprint

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Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. We utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify high-confidence risk genes (HRGs) for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). We subsequently used the Target Central Resource Database (TCRD) to search for drug-protein interactions for these HRGs and previously identified risk genes for alcohol consumption. We identified several HRGs for alcohol consumption that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, codes for activin receptor type-2A, which is critical for liver function, and PRKCE, codes for protein kinase C epsilon, which has been linked to alcohol consumption. Furthermore, several previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs that are promising candidates for managing hepatotoxicity (e.g., metformin), highlighting potential candidates for drug repurposing. This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight promising molecular targets and drugs for treating AUD and ALD.

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Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice

Abstract: These results identify lead compounds for development of PKCε inhibitors that reduce alcohol consumption.

Cited by 22 publications

References 30 publications

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

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