Cocaine facilitates PKC maturation by upregulating its phosphorylation at the activation loop in rat striatal neurons in vivo

Abstract

Newly synthesized protein kinase C (PKC) undergoes a series of phosphorylation to render a mature form of the enzyme. It is this mature PKC that possesses the catalytic competence to respond to second messengers for activation and downstream signaling. The first and rate-limiting phosphorylation occurs at a threonine residue in the activation loop (AL), which triggers the rest maturation processing of PKC and regulates PKC activity in response to cellular stimulation. Given the fact that PKC is enriched in striatal neurons, we investigated the regulation of PKC phosphorylation at the AL site in the rat striatum by the psychostimulant cocaine in vivo. We found that PKC was phosphorylated at the AL site at a moderate level in the normal rat brain. Acute systemic injection of cocaine increased the PKC-AL phosphorylation in the two striatal structures (caudate putamen and nucleus accumbens). Cocaine also elevated the PKC-AL phosphorylation in the medial prefrontal cortex. The cocaine-stimulated PKC phosphorylation in the striatum is rapid and transient. A reliable increase in PKC phosphorylation was seen 7 min after drug injection, which declined to the normal level by 1 h. This kinetics corresponds to that seen for another striatum-enriched protein kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase, in response to cocaine. This study suggests a new model for exploring the impact of cocaine on protein kinases in striatal neurons. By modifying PKC phosphorylation at the AL site, cocaine is believed to possess the ability to alter the maturation processing of the kinase in striatal neurons in vivo.

Protein kinase Cβ is a modulator of the dopamine D2 autoreceptor‐activated trafficking of the dopamine transporter

“…Cocaine has been shown to facilitate PKC maturation to prime PKC for response to the second messenger system (Xue et al . ).…”

“…PKCbII activation by quinpirole is likely because of activation of Phospholipase C beta (PLCb) by the Gbc subunit of Ga i/o (Liu et al 2003). Cocaine has been shown to facilitate PKC maturation to prime PKC for response to the second messenger system (Xue et al 2012). Both D2autoR and DAT are subject to PKC regulation and contain identified PKC phosphorylation sites (Foster et al 2002;Morris et al 2007).…”

Oleic acid enhances the motility of umbilical cord blood derived mesenchymal stem cells through EphB2-dependent F-actin formation

“…Given that GPR40 couples with G proteins [29], we analyzed whether OA induces the phosphorylation and translocation of protein kinase C (PKC) isotypes. Phosphorylation of hydrophobic sites on PKC causes PKCs to become primed for activation, which is referred to as PKC maturation [30]. OA increased the phosphorylation of PKC from 15 to 60 min (Fig.…”

Ruboxistaurin Reduces Cocaine-Stimulated Increases in Extracellular Dopamine by Modifying Dopamine-Autoreceptor Activity

“…We previously reported similar results for the inhibition of amphetamine-evoked activities by two selective PKCβ inhibitors, ruboxistaurin and enzastaurin . The effect of the PKC inhibitors is attributed to the inhibition of amphetamine-stimulated phosphorylation, which would then reduce reverse transport through the DAT. ,, Activation of PKC by cocaine in the striatum and nucleus accumbens has been demonstrated, but the effect is indirect through the activation of dopamine receptors. , Acute cocaine had no effect on PKC activity in the medial prefrontal cortex …”