Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in medium spiny neurons

[Speaker] Xinjian Zhang:1
[Co-author] Taku Nagai:2, Rijwan Uddin Ahammad:1, Keisuke Kuroda:1, Shinichi Nakamuta:1, Takashi Nakano:3, Mutsuki Amano:1, Junichiro Yoshimoto:3,4, Kiyofumi Yamada:2, Kozo Kaibuchi:1
1:Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Japan, 2:Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Japan, 3:Graduate School of Information Science, Nara Institute of Science and Technology, Japan, 4:Neural Computation Unit, Okinawa Institute of Science and Technology Graduate University, Japan

Medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) or D2 receptor (D2R) are a major component of the striatum. In the ventral striatum, D1R-MSNs are involved in rewarding behavior, while D2R-MSNs are involved in aversive behavior. Stimulation of D1R activates protein kinase A (PKA) through Golf to increase neuronal activity, while D2R stimulation inhibits PKA through Gi. In addition to dopamine, adenosine signals also regulate MSNs. The adenosine A2a receptor (A2aR) coupled to Golf is highly and selectively expressed in D2R-MSNs. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap S563 phosphorylation to monitor PKA activity and examined dopamine and adenosine signals in MSNs. We found that a D1R agonist increased Rap1gap phosphorylation in striatal slices and in D1R-MSNs in vivo. The A2aR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. The A2aR agonist showed minimal effects on Rap1gap phosphorylation in vivo, whereas the D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs, and pretreatment with the A2aR antagonist SCH58261 blocked this effect. These results suggest that adenosine positively regulates PKA activity in D2R-MSNs through A2aR, but this effect is blocked by dopamine in basal conditions in vivo. Computational model analysis revealed that the balance between dopamine and adenosine signals regulates Rap1gap phosphorylation in D2R-MSNs. Because adenosine levels are relatively stable in the striatum, a shift from D1R-MSNs to D2R-MSNs or the inverse effect appears to depend on a decrease or increase in dopamine concentration.

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