TY - JOUR
T1 - Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors
AU - Funahashi, Yasuhiro
AU - Ariza, Anthony
AU - Emi, Ryosuke
AU - Xu, Yifan
AU - Shan, Wei
AU - Suzuki, Ko
AU - Kozawa, Sachi
AU - Ahammad, Rijwan Uddin
AU - Wu, Mengya
AU - Takano, Tetsuya
AU - Yura, Yoshimitsu
AU - Kuroda, Keisuke
AU - Nagai, Taku
AU - Amano, Mutsuki
AU - Yamada, Kiyofumi
AU - Kaibuchi, Kozo
N1 - Funding Information:
We thank Dr. M.E. Greenberg for providing Npas4 KO/flox mice and Dr. K. Kobayashi for providing Drd1-mVenus/Drd2-mVenus transgenic mice. We are grateful to T. Watanabe, D. Tsuboi, T. Nishioka, Y. Yamahashi, X. Zhang, E. Hossen, M. Taguchi, K. Hada, and other Kaibuchi and Yamada lab members for helpful discussions and preparation of some materials; F. Ishidate for help with image acquisition; K. Taki for help with MS data acquisition; and T. Ishii for secretarial assistance. We also thank the Division for Research on Laboratory Animals and Medical Research Engineering of Nagoya University Graduate School of Medicine. This work was supported by the following funding sources: “Bioinformatics for Brain Sciences” performed under the SRPBS from MEXT and AMED ; AMED grant numbers JP18dm0207005 , JP19dm0207075 , and JP19dm0307025 ; JSPS KAKENHI grant numbers JP16K18393 , JP17H01380 , JP17J09461 , JP17K07383 , JP17H02220 , JP17K19483 , JP18K14816 , and JP18K14849 ; MEXT KAKENHI grant numbers JP17H05561 and JP19H05209 ; Uehara Memorial Foundation ; and Takeda Science Foundation .
PY - 2019/12/3
Y1 - 2019/12/3
N2 - 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. Funahashi et al. isolate and concentrate a transcriptional factor from the mouse striatum using affinity beads coated with CBP and identify more than 400 CBP-interacting proteins, including Npas4. MAPK phosphorylates Npas4 in D1R-MSNs and increases the interaction between Npas4 and CBP, thereby regulating transcriptional activity to enhance reward-related learning and memory.
AB - 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. Funahashi et al. isolate and concentrate a transcriptional factor from the mouse striatum using affinity beads coated with CBP and identify more than 400 CBP-interacting proteins, including Npas4. MAPK phosphorylates Npas4 in D1R-MSNs and increases the interaction between Npas4 and CBP, thereby regulating transcriptional activity to enhance reward-related learning and memory.
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U2 - 10.1016/j.celrep.2019.10.116
DO - 10.1016/j.celrep.2019.10.116
M3 - Article
C2 - 31801086
AN - SCOPUS:85075838499
VL - 29
SP - 3235-3252.e9
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 10
ER -