Protein kinase C is a modulator of the dopamine D2 autoreceptor-activated trafficking of the dopamine transporter

The strength and duration of extracellular dopamine concentrations are regulated by the presynaptic dopamine transporter (DAT) and dopamine D2 autoreceptors (D2autoRs). There is a functional interaction between these two proteins. Activation of D2autoRs increases DAT trafficking to the surface whereas disruption of this interaction compromises activities of both proteins and alters dopaminergic transmission. Previously we reported that DAT expression and activity are subject to modulation by protein kinase C (PKC). Here, we further demonstrate that PKC is integral for the interaction between DAT and D2autoR. Inhibition or absence of PKC abolished the communication between DAT and D2autoR. In mouse striatal synaptosomes and transfected N2A cells, the D2autoR-stimulated membrane insertion of DAT was abolished by PKC inhibition. Moreover, D2autoR-stimulated DAT trafficking is mediated by a PKC-extracellular signal-regulated kinase signaling cascade where PKC is upstream of extracellular signal-regulated kinase. The increased surface DAT expression upon D2autoR activation resulted from enhanced DAT recycling as opposed to reduced internalization. Further, PKC promoted accelerated DAT recycling. Our study demonstrates that PKC critically regulates D2autoR-activated DAT trafficking and dopaminergic signaling. PKC is a potential drug target for correcting abnormal extracellular dopamine levels in diseases such as drug addiction and schizophrenia.