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

被引：78

作者：

Nagai, Taku ^{[1
,2
,11
]}

Nakamuta, Shinichi ^{[3
,11
]}

Kuroda, Keisuke ^{[3
,11
]}

Nakauchi, Sakura ^{[3
,11
]}

Nishioka, Tomoki ^{[3
,11
]}

Takano, Tetsuya ^{[3
,11
]}

Zhang, Xinjian ^{[3
]}

Tsuboi, Daisuke ^{[3
,11
]}

Funahashi, Yasuhiro ^{[3
,11
]}

Nakano, Takashi ^{[4
,11
]}

Yoshimoto, Junichiro ^{[5
,11
]}

Kobayashi, Kenta ^{[6
]}

Uchigashima, Motokazu ^{[7
]}

Watanabe, Masahiko ^{[7
]}

Miura, Masami ^{[8
]}

Nishi, Akinori ^{[9
,11
]}

Kobayashi, Kazuto ^{[10
]}

Yamada, Kiyofumi ^{[1
,2
,11
]}

Amano, Mutsuki ^{[3
,11
]}

Kaibuchi, Kozo ^{[3
,11
]}

机构：

[1] Nagoya Univ, Grad Sch Med, Dept Neuropsychopharmacol, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

[2] Nagoya Univ, Grad Sch Med, Hosp Pharm, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

[3] Nagoya Univ, Grad Sch Med, Dept Cell Pharmacol, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

[4] Grad Univ, Okinawa Inst Sci & Technol, Neurobiol Res Unit, Onna, Okinawa 9040495, Japan

[5] Grad Univ, Okinawa Inst Sci & Technol, Neural Computat Unit, Onna, Okinawa 9040495, Japan

[6] Natl Inst Physiol Sci, Sect Viral Vector Dev, 38 Nishigonaka Myodaiji, Okazaki, Aichi 4448585, Japan

[7] Hokkaido Univ, Grad Sch Med, Dept Anat, Kita Ku, Kita 15,Nishi 7, Sapporo, Hokkaido 0608638, Japan

[8] Tokyo Metropolitan Inst Gerontol, Neuropathophysiol Res Grp, Itabashi Ku, 35-2 Sakae Cho, Tokyo 1730015, Japan

[9] Kurume Univ, Sch Med, Dept Pharmacol, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan

[10] Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Mol Genet, 1 Hikariga Oka, Fukushima 9601295, Japan

[11] Japan Agcy Med Res & Dev, SRPBS, Chiyoda Ku, AMED 1-7-1 Otemachi, Tokyo 1000004, Japan

来源：

NEURON | 2016年 / 89卷 / 03期

关键词：

NUCLEUS-ACCUMBENS NEURONS; PROTEIN-PHOSPHORYLATION SYSTEMS; MEDIUM SPINY NEURONS; BASAL GANGLIA; STRUCTURAL PLASTICITY; SYNAPTIC PLASTICITY; EXCHANGE FACTOR; CALDAG-GEFI; MAP KINASE; REGIONAL DISTRIBUTION;

D O I：

10.1016/j.neuron.2015.12.019

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：550 / 565

页数：16

共 74 条

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