Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior

Daisuke Tsuboi, Takeshi Otsuka, Takushi Shimomura, Md Omar Faruk, Yukie Yamahashi, Mutsuki Amano, Yasuhiro Funahashi, Keisuke Kuroda, Tomoki Nishioka, Kenta Kobayashi, Hiromi Sano, Taku Nagai, Kiyofumi Yamada, Anastasios V. Tzingounis, Atsushi Nambu, Yoshihiro Kubo, Yasuo Kawaguchi, Kozo Kaibuchi

研究成果: Article査読

1 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号111309
ジャーナルCell Reports
40
10
DOI
出版ステータスPublished - 06-09-2022

All Science Journal Classification (ASJC) codes

  • 生化学、遺伝学、分子生物学(全般)

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