Cocaine Reward Controlled by Dopamine-Activated Rap1 Signaling Pathway in Striatal Neurons

A Nagoya University (Japan) research team, together with colleagues from other institutions, has discovered how dopamine controls the brain’s response to cocaine in a mouse model. A new report shows that cocaine administration increases dopamine levels in the striatum, activating a signaling pathway that was previously unknown—the Rap1 signaling pathway. The research was published in the February 3, 2016 issue of Neuron. The article is titled “Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation As a Reward Signal In Vivo.” Dopamine is known to activate a protein called PKA in striatal neurons, which, in turn, activates many additional substrates to regulate neuronal excitability and control behavior. However, the identities of the PKA substrates were not previously known. The Nagoya-led research team has now uncovered some answers. “We stimulated PKA in mouse brain slices to activate these unknown substrates,” explains corresponding author Kozo Kaibuchi, Ph.D., of the University of Nagoya’s Department of Cell Pharmacology. His research team was able to extract these activated proteins from brain slices and to identify them. “Using this screening approach, we identified more than 100 candidate substrates of PKA,” continues Dr. Kaibuchi. One of these novel candidates was Rasgrp2, a protein that is highly expressed in striatal neurons. Rasgrp2 positively regulates another protein called Rap1 and the authors were intrigued to find out whether Rap1 was activated by Rasgrp2 in striatal neurons as a result of cocaine administration. Through a range of experiments, the Nagoya-led research group found the answer; the scientists demonstrated that cocaine treatment increased the phosphorylation of Rasgrp2 by PKA, and phosphorylated Rasgrp2, in turn, activated Rap1 in striatal neurons.
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