MAPKによるNpas4のリン酸化は報酬関連の遺伝子発現と行動を制御する

• Published in: 日本薬理学会年会要旨集 p. 1-YIA-26
• Main Authors: 単, 偉, 永井, 拓, 天野, 睦紀, 黒田, 啓介, 小澤, 祥, アハマド, リジュワン ウッディン, 高野, 哲也, 貝淵, 弘三, アリザ, アンソニー, 由良, 義光, 山田, 清文, 許, 伊凡, 呉, 夢雅, 恵美, 亮佑, 船橋, 靖広
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2020
• Subjects: behavior; dopamine; gene expression; phosphorylation
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.93.0_1-YIA-26

Dopamine (DA) activates MAPK via PKA/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R)in the nucleus accumbens (NAc), thereby regulating reward-related behavior.However, howMAPKregulates reward-relatedlearning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we performed proteomic analysis using affinity beads coated with CREB-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identified more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4 (Npas4). We found that MAPK phosphorylated Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. The deletion of Npas4 in D1R-expressing MSNs impaired cocaine-induced place preference, which was rescued by Npas4-WT but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases transcriptional activity to enhance reward-related learning and memory. (Funahashi et al., Cell Reports, 2019)