論文

査読有り
2016年2月

Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo

NEURON
  • Taku Nagai
  • Shinichi Nakamuta
  • Keisuke Kuroda
  • Sakura Nakauchi
  • Tomoki Nishioka
  • Tetsuya Takano
  • Xinjian Zhang
  • Daisuke Tsuboi
  • Yasuhiro Funahashi
  • Takashi Nakano
  • Junichiro Yoshimoto
  • Kenta Kobayashi
  • Motokazu Uchigashima
  • Masahiko Watanabe
  • Masami Miura
  • Akinori Nishi
  • Kazuto Kobayashi
  • Kiyofumi Yamada
  • Mutsuki Amano
  • Kozo Kaibuchi
  • 全て表示

89
3
開始ページ
550
終了ページ
565
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.neuron.2015.12.019
出版者・発行元
CELL PRESS

Dopamine (DA) type 1 receptor (D1R) signaling in the striatum presumably regulates neuronal excitability and reward-related behaviors through PKA. However, whether and how D1Rs and PKA regulate neuronal excitability and behavior remain largely unknown. Here, we developed a phosphoproteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than 100 candidate substrates, including Rap1 GEF (Rasgrp2). We found that PKA phosphorylation of Rasgrp2 activated its guanine nucleotide-exchange activity on Rap1. Cocaine exposure activated Rap1 in the nucleus accumbens in mice. The expression of constitutively active PKA or Rap1 in accumbal D1R-expressing medium spiny neurons (D1R-MSNs) enhanced neuronal firing rates and behavioral responses to cocaine exposure through MAPK. Knockout of Rap1 in the accumbal D1R-MSNs was sufficient to decrease these phenotypes. These findings demonstrate a novel DA-PKA-Rap1-MAPK intracellular signaling mechanism in D1R-MSNs that increases neuronal excitability to enhance reward-related behaviors.

リンク情報
DOI
https://doi.org/10.1016/j.neuron.2015.12.019
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000373564900014&DestApp=WOS_CPL
ID情報
  • DOI : 10.1016/j.neuron.2015.12.019
  • ISSN : 0896-6273
  • eISSN : 1097-4199
  • Web of Science ID : WOS:000373564900014

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