MEK/mTOR-dependent D1 dopamine receptor activation induces local protein synthesis via eEF2 dephosphorylation in neurons

Neuromodulators in general, and dopamine in particular, define brain and neuronal states in different ways including regulation of global and local mRNA translation. Yet, the signaling pathways underlying the effects of dopamine on mRNA translation are not clear. Here, using genetic, pharmacologic, biochemical, and imaging methods, we tested the hypothesis that dopamine regulates phosphorylation of the eukaryotic elongation factor 2 (eEF2). We found that activation of dopamine receptor D1 but not D2 leads to rapid dephosphorylation of eEF2 at Thr 56 in cortical primary neuronal culture and in vivo in a time-dependent manner. Additionally, NMDA receptor, mTOR, and ERK pathways are upstream to the D1 receptor-dependent eEF2 dephosphorylation and essential for it. Furthermore, D1 receptor activation resulted in a major reduction in dendritic eEF2 phosphorylation levels together with a correlative increase in local mRNA translation. These results reveal the role of eEF2 in dopamine regulation of local mRNA translation in neurons. One-sentence summary D1 receptor activation increases protein synthesis in dendrites by inactivating eEF2K in an ERK2/mTOR-dependent manner.