Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors
Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors
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DOI：
10.1016/j.celrep.2019.10.116
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发表时间：
2019-12-03
期刊：
影响因子：
8.8
通讯作者：
Kaibuchi, Kozo
中科院分区：
文献类型：
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作者：
Funahashi, Yasuhiro;Ariza, Anthony;Kaibuchi, Kozo
多巴胺(DA)通过蛋白激酶A(PKA)/RAP1激活伏核(NAC)中表达多巴胺D1受体(D1R)的中型棘神经元(MSN)中的丝裂原活化蛋白激酶(MAPK)，从而调节奖赏相关行为。然而，MAPK如何通过基因表达来调节与奖赏相关的学习和记忆，目前还知之甚少。在这里，为了确定相关的转录因子，我们使用包被环磷酸腺苷反应元件结合蛋白(CREB)结合蛋白(CBP)的亲和珠进行蛋白质组学分析，CBP是一种参与奖赏相关行为的转录辅助激活因子。我们鉴定了400多种CBP相互作用蛋白，包括神经元每Arnt Sim结构域蛋白4(Npas4)。我们发现，MAPK使PKA下游的Npas4磷酸化，增加了Npas4与CBP的相互作用，并增强了Npas4在脑源性神经营养因子(BDNF)启动子上的转录活性。在表达D1R的MSN中，Npas4的缺失削弱了可卡因诱导的位置偏爱，这种偏爱可被Npas4野生型(WT)拯救，但不被磷缺乏的Npas4突变体拯救。这些观察表明，MAPK使D1R-MSN中的Npas4磷酸化，并增加转录活性，以增强与奖励相关的学习和记忆。
Dopamine (DA) activates mitogen-activated protein kinase (MAPK) via protein kinase A (PKA)/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), thereby regulating reward-related behavior. However, how MAPK regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we perform proteomic analysis using affinity beads coated with cyclic AMP response element binding protein (CREB)-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identify more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4 (Npas4). We find that MAPK phosphorylates 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 impairs cocaine-induced place preference, which is rescued by Npas4-wild-type (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.