TY - JOUR
T1 - Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons
AU - Zhang, Xinjian
AU - Nagai, Taku
AU - Ahammad, Rijwan Uddin
AU - Kuroda, Keisuke
AU - Nakamuta, Shinichi
AU - Nakano, Takashi
AU - Yukinawa, Naoto
AU - Funahashi, Yasuhiro
AU - Yamahashi, Yukie
AU - Amano, Mutsuki
AU - Yoshimoto, Junichiro
AU - Yamada, Kiyofumi
AU - Kaibuchi, Kozo
N1 - Funding Information:
We thank Dr. Kazuto Kobayashi for providing Drd1-mVenus / Drd2-mVenus transgenic mice. We thank Drs. Akinori Nishi and Md. Hasanuzzaman Shohag for technical advice. We wish to acknowledge Sachi Kozawa, Miki Taguchi, Division for Medical Research Engineering and Division of Experimental Animals at Nagoya University Graduate School of Medicine for technical assistance. We also thank Takako Ishii for secretarial assistance. This work was supported by the following funding sources: “Bioinformatics for Brain Sciences” performed under the SRPBS from MEXT and AMED , “Brain/MINDS” from AMED , JSPS KAKENHI Grant Number [ 17J10615 ], [ 17H01380 ], [ 17H02220 ], [ 15K06772 ], [ 17K19483 ], [ 16K18393 ], MEXT KAKENHI Grant Number [ 17H05561 ] and Joint Research by the National Institutes of Natural Sciences , Grant number [ 01111706 ].
Publisher Copyright:
© 2018 The Authors
PY - 2019/1
Y1 - 2019/1
N2 - Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through Golf to increase neuronal activity, while D2R stimulation inhibits PKA through Gi. Adenosine A2A receptor (A2AR) coupled to Golf is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 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. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.
AB - Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through Golf to increase neuronal activity, while D2R stimulation inhibits PKA through Gi. Adenosine A2A receptor (A2AR) coupled to Golf is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 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. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.
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U2 - 10.1016/j.neuint.2018.10.008
DO - 10.1016/j.neuint.2018.10.008
M3 - Article
C2 - 30336179
AN - SCOPUS:85055745473
VL - 122
SP - 8
EP - 18
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
ER -