TY - JOUR
T1 - Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior
AU - Tsuboi, Daisuke
AU - Otsuka, Takeshi
AU - Shimomura, Takushi
AU - Faruk, Md Omar
AU - Yamahashi, Yukie
AU - Amano, Mutsuki
AU - Funahashi, Yasuhiro
AU - Kuroda, Keisuke
AU - Nishioka, Tomoki
AU - Kobayashi, Kenta
AU - Sano, Hiromi
AU - Nagai, Taku
AU - Yamada, Kiyofumi
AU - Tzingounis, Anastasios V.
AU - Nambu, Atsushi
AU - Kubo, Yoshihiro
AU - Kawaguchi, Yasuo
AU - Kaibuchi, Kozo
N1 - Funding Information:
We are grateful to T. Watanabe, X. Zhang, M. Taguchi, N. Mishima, H. Koshimizu, and other Kaibuchi and Yamada laboratory members for helpful discussions and preparation of some study materials, K. Taki for help with MS data acquisition, and T. Ishii for secretarial assistance. We also thank the Division for Research on Laboratory Animals and Medical Research Engineering of Nagoya University Graduate School of Medicine and the Education and Research Center of Animal Models for Human Diseases in Fujita Health University. This work was supported by the following funding sources: “Bioinformatics for Brain Sciences” performed under the SRPBS from MEXT and AMED; AMED grant nos. JP18dm0207005, JP19dm0207075, JP21wm0425017, JP21dm0207115, and JP21wm0425008; JSPS KAKENHI grant nos JP16K18393, JP17H01380, JP17K07383, JP17H02220, JP17K19483, JP18K14849, JP19K16370, JP21K06428, and JP21K06427; MEXT KAKENHI grant nos JP17H05561, JP19H05209, and JP21H00196; Uehara Memorial Foundation (FV2021); Takeda Science Foundation (2600900064); a grant from the NINS Joint Research Program (01111706); and a grant-in-aid from the Hori Sciences & Arts Foundation (FV2019). Conceptualization, D.T. T.O. and K. Kaibuchi; methodology, T.S. Y.Y. K. Kuroda, Y.F. T.N. T.N. K.Y. A.V.T. and K. Kobayashi; formal analysis, D.T. T.O. and O.F.; investigation, D.T. T.O. K. Kuroda, M.A. and T.S.; resources, K. Kobayashi, K.Y. A.V.T. Y. Kubo, Y.F. H.S. A.N. and Y. Kawaguchi; data curation, D.T. T.O. T.N. H.S. A.N. Y. Kubo, and Y. Kawaguchi; writing – original draft, D.T. T.O. H.K. and K. Kaibuchi. The authors declare no competing interests.
Funding Information:
We are grateful to T. Watanabe, X. Zhang, M. Taguchi, N. Mishima, H. Koshimizu, and other Kaibuchi and Yamada laboratory members for helpful discussions and preparation of some study materials, K. Taki for help with MS data acquisition, and T. Ishii for secretarial assistance. We also thank the Division for Research on Laboratory Animals and Medical Research Engineering of Nagoya University Graduate School of Medicine and the Education and Research Center of Animal Models for Human Diseases in Fujita Health University. This work was supported by the following funding sources: “Bioinformatics for Brain Sciences” performed under the SRPBS from MEXT and AMED; AMED grant nos. JP18dm0207005 , JP19dm0207075 , JP21wm0425017 , JP21dm0207115 , and JP21wm0425008 ; JSPS KAKENHI grant nos JP16K18393 , JP17H01380 , JP17K07383 , JP17H02220 , JP17K19483 , JP18K14849 , JP19K16370 , JP21K06428 , and JP21K06427 ; MEXT KAKENHI grant nos JP17H05561 , JP19H05209 , and JP21H00196 ; Uehara Memorial Foundation ( FV2021 ); Takeda Science Foundation ( 2600900064 ); a grant from the NINS Joint Research Program ( 01111706 ); and a grant-in-aid from the Hori Sciences & Arts Foundation ( FV2019 ).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/9/6
Y1 - 2022/9/6
N2 - Dysfunctional dopamine signaling is implicated in various neuropsychological disorders. Previously, we reported that dopamine increases D1 receptor (D1R)-expressing medium spiny neuron (MSN) excitability and firing rates in the nucleus accumbens (NAc) via the PKA/Rap1/ERK pathway to promote reward behavior. Here, the results show that the D1R agonist, SKF81297, inhibits KCNQ-mediated currents and increases D1R-MSN firing rates in murine NAc slices, which is abolished by ERK inhibition. In vitro ERK phosphorylates KCNQ2 at Ser414 and Ser476; in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion of Kcnq2 in D1R-MSNs reduces the inhibitory effect of SKF81297 on KCNQ channel activity, while enhancing neuronal excitability and cocaine-induced reward behavior. These effects are restored by wild-type, but not phospho-deficient KCNQ2. Hence, D1R-ERK signaling controls MSN excitability via KCNQ2 phosphorylation to regulate reward behavior, making KCNQ2 a potential therapeutical target for psychiatric diseases with a dysfunctional reward circuit.
AB - Dysfunctional dopamine signaling is implicated in various neuropsychological disorders. Previously, we reported that dopamine increases D1 receptor (D1R)-expressing medium spiny neuron (MSN) excitability and firing rates in the nucleus accumbens (NAc) via the PKA/Rap1/ERK pathway to promote reward behavior. Here, the results show that the D1R agonist, SKF81297, inhibits KCNQ-mediated currents and increases D1R-MSN firing rates in murine NAc slices, which is abolished by ERK inhibition. In vitro ERK phosphorylates KCNQ2 at Ser414 and Ser476; in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion of Kcnq2 in D1R-MSNs reduces the inhibitory effect of SKF81297 on KCNQ channel activity, while enhancing neuronal excitability and cocaine-induced reward behavior. These effects are restored by wild-type, but not phospho-deficient KCNQ2. Hence, D1R-ERK signaling controls MSN excitability via KCNQ2 phosphorylation to regulate reward behavior, making KCNQ2 a potential therapeutical target for psychiatric diseases with a dysfunctional reward circuit.
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U2 - 10.1016/j.celrep.2022.111309
DO - 10.1016/j.celrep.2022.111309
M3 - Article
C2 - 36070693
AN - SCOPUS:85137097992
VL - 40
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 10
M1 - 111309
ER -