Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes.

We have reported that inhibition of protein kinase C blocks the Ca(2+)-independent reverse transport of dopamine mediated by amphetamine. In this study we investigated whether activation of protein kinase C by 12-O-tetradecanoyl phorbol-13-acetate (TPA) would mediate dopamine release through the plasmalemmal dopamine transporter. TPA, at 250 nM, increased the release of dopamine from rat striatal slices and synaptosomes while the inactive phorbol ester, 4alpha-phorbol, was ineffective. The TPA-mediated dopamine release was independent of extracellular calcium and was blocked by a selective protein kinase C inhibitor, Ro31-8220. The dopamine transporter antagonists, cocaine and GBR 12935 blocked the TPA-mediated dopamine release. In addition, cocaine blocked TPA-mediated phosphorylation of the plasmalemmal dopamine transporter. These results suggest that activation of protein kinase C results in reverse transport of dopamine through the plasmalemmal dopamine transporter and the phosphorylated substrate could be the dopamine transporter.