Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCε-Dependent ERK Activation and TRBP Phosphorylation

Previously we have shown that morphine regulates adult neurogenesis by modulating miR-181a maturation and subsequent hippocampal neural progenitor cell (NPC) lineages. Using NPCs cultured from PKC epsilon or beta-arrestin2 knockout mice and the MAPK/ERK kinase inhibitor U0126, we demonstrate that regulation of NPC differentiation via the miR-181a/Prox1/Notch1 pathway exhibits ligand-dependent selectivity. In NPCs, morphine and fentanyl activate ERK via the PKC epsilon- and beta-arrestin-dependent pathways, respectively. After fentanyl exposure, the activated phospho-ERK translocates to the nucleus. Conversely, after morphine treatment, phospho-ERK remains in the cytosol and is capable of phosphorylating TAR RNA-binding protein (TRBP), a cofactor of Dicer. This augments Dicer activity and promotes the maturation of miR-181a. Furthermore, using NPCs transfected with wild-type TRBP, S Delta A, and S Delta D TRBP mutants, we confirmed the crucial role of TRBP phosphorylation in Dicer activity, miR-181a maturation, and finally the morphine-induced astrocyte-preferential differentiation of NPCs. Thus, morphine modulates the lineage-specific differentiation of NPCs by PKC epsilon-dependent ERK activation with subsequent TRBP phosphorylation and miR-181a maturation.