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Neuron. 2016 Feb 3;89(3):550-65. doi: 10.1016/j.neuron.2015.12.019. Epub 2016 Jan 21.

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

Author information

1
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; SRPBS, Japan Agency for Medical Research and Development, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
2
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; SRPBS, Japan Agency for Medical Research and Development, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
3
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
4
Neurobiology Research Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan; SRPBS, Japan Agency for Medical Research and Development, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
5
Neural Computation Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan; SRPBS, Japan Agency for Medical Research and Development, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
6
Section of Viral Vector Development, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki 444-8585, Japan.
7
Department of Anatomy, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
8
Neuropathophysiology Research Group, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
9
Department of Pharmacology, School of Medicine, Kurume University, 67 Asahi-machi, Kurume 830-0011, Japan; SRPBS, Japan Agency for Medical Research and Development, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
10
Department of Molecular Genetics, Institute of Biomedical Sciences, School of Medicine, Fukushima Medical University, 1 Hikariga-oka, Fukushima 960-1295, Japan.
11
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; SRPBS, Japan Agency for Medical Research and Development, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: kaibuchi@med.nagoya-u.ac.jp.

Abstract

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.

PMID:
26804993
DOI:
10.1016/j.neuron.2015.12.019
[Indexed for MEDLINE]
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