Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo
| Autor: | Masami Miura, Yasuhiro Funahashi, Masahiko Watanabe, Taku Nagai, Tomoki Nishioka, Motokazu Uchigashima, Junichiro Yoshimoto, Xinjian Zhang, Keisuke Kuroda, Kiyofumi Yamada, Tetsuya Takano, Daisuke Tsuboi, Kenta Kobayashi, Mutsuki Amano, Sakura Nakauchi, Takashi Nakano, Kazuto Kobayashi, Kozo Kaibuchi, Shinichi Nakamuta, Akinori Nishi |
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| Rok vydání: | 2016 |
| Předmět: |
Proteomics
0301 basic medicine MAPK/ERK pathway endocrine system Proteome Dopamine Neuroscience(all) Action Potentials Striatum Biology Nucleus accumbens Medium spiny neuron Nucleus Accumbens Mice 03 medical and health sciences 0302 clinical medicine Cocaine Reward medicine Animals Guanine Nucleotide Exchange Factors Phosphorylation Extracellular Signal-Regulated MAP Kinases Receptor Mice Knockout Neurons Receptors Dopamine D1 General Neuroscience Colforsin Phosphoproteomics rap1 GTP-Binding Proteins Benzazepines Phosphoproteins Cyclic AMP-Dependent Protein Kinases Corpus Striatum Enzyme Activation enzymes and coenzymes (carbohydrates) 030104 developmental biology Neuroscience 030217 neurology & neurosurgery Intracellular Signal Transduction medicine.drug |
| Zdroj: | Neuron. 89(3):550-565 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2015.12.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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