Ethanol-Induced Changes in PKCε: From Cell to Behavior - PubMed (original) (raw)

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Ethanol-Induced Changes in PKCε: From Cell to Behavior

Rashidi M Pakri Mohamed et al. Front Neurosci. 2018.

Abstract

The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCε is the most implicated in ethanol-induced biochemical and behavioral changes. Ethanol exposure causes changes to PKCε expression and localization in various brain regions that mediate addiction-favoring plasticity. Ethanol works in conjunction with numerous upstream kinases and second messenger activators to affect cellular PKCε expression. Chauffeur proteins, such as receptors for activated C kinase (RACKs), cause the translocation of PKCε to aberrant sites and mediate ethanol-induced changes. In this article, we aim to review the following: the general structure and function of PKCε, ethanol-induced changes in PKCε expression, the regulation of ethanol-induced PKCε activities in DAG-dependent and DAG-independent environments, the mechanisms underlying PKCε-RACKε translocation in the presence of ethanol, and the existing literature on the role of PKCε in ethanol-induced neurobehavioral changes, with the goal of creating a working model upon which further research can build.

Keywords: PKC; PKCε; RACK; alcohol; epsilon; ethanol.

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Figures

Figure 1

Figure 1

Signaling pathway of ethanol-mediated changes in PKCε activities (expression and translocation). Interaction of ethanol with GPCR results in generation of second messengers such as DAG and IP3. Long-term ethanol consumption upregulates cellular levels of basal PKCε and upstream kinases such as PI3K and mTORC2 which collectively increases phosohorylation of PKCε at S729. In DAG-dependent pathway, binding of DAG and RACK to mature PKCε translocates the kinase to distinct subcellular target sites to mediate downstream signaling pathways. In DAG-independent pathway, increase in DAG kinase activities causes generation of PA which could affect PKCε translocation via novel pathways. Once translocated, PKCε could affect downstream signaling through phosphorylation of numerous molecular targets which include GABAA, N-ethylmaleimide sensitif factor and mGlu5 which influence binge ethanol consumption. PKCε also causes internalization of mGlu5 surface receptors that could potentially reduce mGlu5 availability during abstinence.

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