Protein kinase C[Latin Small Letter Open E] activity regulates mGluR5 surface expression in the rat nucleus accumbens

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Metabotropic glutamate receptors, including the type 5 receptor (mGluR5), modulate neurotransmission at the majority of excitatory synapses in the brain. mGluR5 are coupled via Gαq/11 proteins to phospholipase C‐ and diacylglycerol‐mediated cellular signaling, release of intracellular calcium and activation of a number of protein kinases (Niswender and Conn, 2010). One of the key kinases activated by mGluR5 is protein kinase C (PKC; Abe et al., 1992; Pin et al., 1994). Up to 12 PKC isoforms have been identified to date in mammals, suggesting a diverse array of functions. PKC isoforms are typically grouped into four subfamilies, conventional (α, βI, βII, and γ), novel (δ, [Latin Small Letter Open E], η, θ), atypical (ζ, λ/ι), and PKC‐related kinases1–3, based on their structural features and sensitivity to regulatory effects of second messengers Ca2+ and diacylglycerol (Newton, 2010; Rosse et al., 2010). In this regard, PKC[Latin Small Letter Open E] activation is dependent on the availability of diacylglycerol generated downstream of Gαq/11‐coupled GPCRs, including mGluR1/5 (Newton and Messing, 2010). Upon activation, PKC[Latin Small Letter Open E] is redistributed to various cellular compartments, including the cell membrane, in a process called translocation. It is believed that translocation is important for regulation of enzyme activity and substrate specificity, and translocation of PKC isoforms is mediated by isozyme‐specific anchoring proteins such the receptor for activated C kinase (RACK) protein family (Schechtman and Mochly‐Rosen, 2001; Schechtman et al., 2004). Phosphorylation is another important mechanism that regulates PKC[Latin Small Letter Open E] activity (Cenni et al., 2002). PKC[Latin Small Letter Open E] contains several phosphorylation sites that are thought to play critical role in priming kinase activity or delaying kinase degradation (Wang et al., 2016). Previous research shows that PKC[Latin Small Letter Open E] activity can play an important role in cardioprotection during heart failure (Ferreira et al., 2011) and progression of various types of tumors (Jain and Basu, 2014) and in the behavioral response to alcohol (Hodge et al., 1999; Zeidman et al., 2002; Shirai et al., 2008; Migues et al., 2010) and, more recently, cocaine (Miller et al., 2016).
With regard specifically to alcohol, it has been shown that brief exposure of PKC[Latin Small Letter Open E]‐expressing cell lines to alcohol causes enzyme translocation from perinuclear regions to the cytoplasm (Gordon et al., 1997). In animals, binge alcohol drinking elevates phospho‐Ser729‐PKC[Latin Small Letter Open E] levels in both the NAc and the central nucleus of the amygdala in mice (Cozzoli et al., 2015). Cozzoli et al. further demonstrated that inhibition of PKC[Latin Small Letter Open E] translocation within both brain regions reduced binge alcohol consumption in a manner dependent on intact function of mGluR1/5. Likewise, a previous study by our group demonstrated that PKC[Latin Small Letter Open E] is a downstream signaling target of mGluR5 that mediates the ability of mGluR5 antagonists to reduce voluntary alcohol intake when administered systemically (Olive et al., 2005) or into the nucleus accumbens (NAc; Gass and Olive, 2009). These findings suggest that ventral striatal mGluR5 receptors are coupled to PKC[Latin Small Letter Open E] and that in turn activity of PKC[Latin Small Letter Open E] is critical for mGluR5 regulation of alcohol‐related behaviors. However, the nature and the cellular mechanisms of PKC[Latin Small Letter Open E]‐dependent regulation of mGluR5 remain unclear.
In general, activation of PKC results in phosphorylation a number of cellular substrates, including mGluR1/5 (Mao et al., 2008). PKC‐mediated phosphorylation of mGluR1/5 can then lead to receptor desensitization and internalization (Gereau and Heinemann, 1998; Lee et al., 2008; Ko et al., 2012).
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