Reference - Detail
|Author||Nagai T, Nakamuta S, Kuroda K, Nakauchi S, Nishioka T, Takano T, Zhang X, Tsuboi D, Funahashi Y, Nakano T, Yoshimoto J, Kobayashi K, Uchigashima M, Watanabe M, Miura M, Nishi A, Kobayashi K, Yamada K, Amano M, Kaibuchi K.|
|Title||Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo.|
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.
|MeSH||Action Potentials / physiology Animals Benzazepines / pharmacology Cocaine / pharmacology Colforsin / pharmacology Corpus Striatum / drug effects Corpus Striatum / metabolism Cyclic AMP-Dependent Protein Kinases / metabolism Dopamine / metabolism* Dopamine / pharmacology Enzyme Activation Extracellular Signal-Regulated MAP Kinases / metabolism Extracellular Signal-Regulated MAP Kinases / physiology Guanine Nucleotide Exchange Factors / metabolism Mice Mice, Knockout Neurons / metabolism Neurons / physiology Nucleus Accumbens / metabolism Phosphoproteins / metabolism* Phosphorylation / drug effects Proteome / metabolism* Proteomics* Receptors, Dopamine D1 / metabolism* Reward* Signal Transduction* / drug effects rap1 GTP-Binding Proteins / genetics rap1 GTP-Binding Proteins / metabolism*|
|Mice||B6.Cg-Tg(Drd2-YFP)364-5(RBRC02332) C57BL/6J-Tg(mDrd1-YFP)680-1Koba (RBRC03111) B6;129S-Rap1a<tm1Morz> Rap1b<tm1Morz>(RBRC04720)|