RRC ID 82503
Author Funahashi Y, Ariza A, Emi R, Xu Y, Shan W, Suzuki K, Kozawa S, Ahammad RU, Wu M, Takano T, Yura Y, Kuroda K, Nagai T, Amano M, Yamada K, Kaibuchi K.
Title Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors.
Journal Cell Rep
Abstract 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.
Volume 29(10)
Pages 3235-3252.e9
Published 2019-12-3
DOI 10.1016/j.celrep.2019.10.116
PII S2211-1247(19)31449-4
PMID 31801086
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / metabolism* Brain-Derived Neurotrophic Factor / metabolism COS Cells Cell Line Chlorocebus aethiops Cocaine / pharmacology Dopamine / metabolism Female Gene Expression / drug effects Gene Expression / physiology* Male Mice, Inbred C57BL Mice, Inbred ICR Mitogen-Activated Protein Kinases / metabolism* Neurons / drug effects Neurons / metabolism Phosphorylation / drug effects Phosphorylation / physiology* Proteomics / methods Receptors, Dopamine D1 / metabolism Reward Signal Transduction / drug effects Signal Transduction / physiology Transcription, Genetic / drug effects Transcription, Genetic / physiology
Resource
Mice RBRC02332 RBRC03111