Meta-Biol

• Pathways

Based on studies in mouse (Funahashi et al. 2019) and rat (Ooe et al. 2009) model systems, neuronal cell stimulation leads to MAPK1 (and probably MAPK3) mediated phosphorylation of NPAS4 on evolutionarily conserved amino acid residues, which increases transcriptional activity of NPAS4 on target gene promoters such as BDNF, possibly by enabling association of NPAS4 with histone acetyltransferase CREBBP (CBP). Activation of Mapk1/Mapk3 upon Ngf treatment of rat pheochromocytoma cell line PC12 results in Npas4 phosphorylation and increased Npas4 transcriptional activity (Ooe et al. 2009). In mouse medium spiny neurons expressing dopamine D1 receptor (D1R), dopamine activates Mapk1 and Mapk3 via PKA and Rap1 signaling, leading to phosphorylation of nuclear Npas4. In vitro, it was shown that recombinant human MAPK1 phosphorylates mouse Npas4 on six conserved residues: T423, T427, S577, S580, T611, and S615 (positions of these amino acid residues are conserved in human NPAS4). The same residues are phosphorylated in dopamine-treated MSNs expressing D1R and recombinant Npas4. Mapk1/3-mediated phosphorylation of Npas4 promotes its binding to Crebbp (Cbp), which, through an unknown mechanism, increases Npas4-mediated transcription of target genes, such as Bdnf (Funahashi et al. 2019).