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

doi:10.1016/j.celrep.2022.111309

Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior

Cell Rep. 2022 Sep 6;40(10):111309. doi: 10.1016/j.celrep.2022.111309.

Authors

Daisuke Tsuboi¹, Takeshi Otsuka², Takushi Shimomura³, Md Omar Faruk⁴, Yukie Yamahashi¹, Mutsuki Amano⁴, Yasuhiro Funahashi¹, Keisuke Kuroda⁴, Tomoki Nishioka¹, Kenta Kobayashi⁵, Hiromi Sano⁶, Taku Nagai⁷, Kiyofumi Yamada⁸, Anastasios V Tzingounis⁹, Atsushi Nambu¹⁰, Yoshihiro Kubo³, Yasuo Kawaguchi¹¹, Kozo Kaibuchi¹²

Affiliations

¹ Division of Cell Biology, International Center for Brain Science, Fujita Health University, 1-98 Dengakugakubo, Kusukake-cho, Toyoake, Aichi 470-1192, Japan.
² Division of Cerebral Circuitry, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
³ Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
⁴ Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
⁵ Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
⁶ Division of System Neurophysiology, National Institute for Physiological Sciences and Department of Physiological Sciences, Sokendai, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan; Division of Behavioral Neuropharmacology, International Center for Brain Science, Fujita Health University, 1-98 Dengakugakubo, Kusukake-cho, Toyoake, Aichi 470-1192, Japan.
⁷ Division of Behavioral Neuropharmacology, International Center for Brain Science, Fujita Health University, 1-98 Dengakugakubo, Kusukake-cho, Toyoake, Aichi 470-1192, Japan.
⁸ Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan.
⁹ Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
¹⁰ Division of System Neurophysiology, National Institute for Physiological Sciences and Department of Physiological Sciences, Sokendai, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
¹¹ Division of Cerebral Circuitry, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan; Brain Science Institute, Tamagawa University, Machida, Tokyo 194-8610, Japan.
¹² Division of Cell Biology, International Center for Brain Science, Fujita Health University, 1-98 Dengakugakubo, Kusukake-cho, Toyoake, Aichi 470-1192, Japan; Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. Electronic address: kaibuchi@fujita-hu.ac.jp.

PMID: 36070693
DOI: 10.1016/j.celrep.2022.111309

Abstract

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.

Keywords: CP: Neuroscience; KCNQ2; and phosphorylation; dopamine; neuronal excitability; reward.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dopamine* / metabolism
KCNQ2 Potassium Channel* / metabolism
Mental Disorders* / metabolism
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins* / metabolism
Neurons / metabolism
Phosphorylation
Receptors, Dopamine D1 / metabolism
Reward

Substances

KCNQ2 Potassium Channel
Kcnq2 protein, mouse
Nerve Tissue Proteins
Receptors, Dopamine D1
Dopamine