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 - 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
SN - 2211-1247
VL - 40
JO - Cell Reports
JF - Cell Reports
IS - 10
M1 - 111309
ER -