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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.
Highlights
Protein kinases C (PKCs) are a family of protein kinase enzymes that regulate most cellular reactions by controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues (Ohno and Nishizuka, 2002)
We present a broad overview of the roles of upstream kinases, phosphatases, and activators of PKCε and their interactions with ethanol
Several intriguing insights have emerged from PKCε research: Ethanol-PKCε interactions might be DAG-free in some brain regions
Summary
Protein kinases C (PKCs) are a family of protein kinase enzymes that regulate most cellular reactions by controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues (Ohno and Nishizuka, 2002). PKCε is a phorbol ester/diacylglycerol (DAG)-sensitive and calcium-independent serine/threonine kinase. PKCε is abundantly present in regions of the brain that are implicated in drug addiction, such as the frontal cortex, striatum, nucleus accumbens (NAc), and hippocampus (Saito et al, 1993; Minami et al, 2000). PKCε is considered to mediate an ethanol-tolerant phenotype because of its interactions with receptors such as gamma aminobutyric acid (GABAA) (Poisbeau et al, 1999) and metabotropic glutamate receptor subtype 5 (mGlu5)
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