Division of Cell Biology, International Center for Brain Science, Fujita Health University, 1-98 Dengakugakubo, Kusukake-cho, Toyoake, Aichi 470-1192, Japan.
Division of Cerebral Circuitry, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
Cell Rep. 2022 Sep 6;40(10):111309. doi: 10.1016/j.celrep.2022.111309.
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.
多巴胺信号功能障碍与各种神经心理障碍有关。此前，我们报道多巴胺通过蛋白激酶 A（PKA）/Rap1/细胞外信号调节激酶（ERK）通路增加伏隔核（NAc）中表达 D1 受体（D1R）的中脑多巴胺能神经元（MSN）的兴奋性和放电频率，从而促进奖励行为。在这里，研究结果表明，D1 受体激动剂 SKF81297 抑制 KCNQ 介导的电流并增加小鼠 NAc 切片中 D1R-MSN 的放电频率，ERK 抑制可消除这种作用。体外 ERK 在 Ser414 和 Ser476 处使 KCNQ2 磷酸化；在体内，NAc 切片中的多巴胺信号下游使 KCNQ2 磷酸化。在 D1R-MSN 中条件性敲除 Kcnq2 会降低 SKF81297 对 KCNQ 通道活性的抑制作用，同时增强神经元兴奋性和可卡因诱导的奖励行为。野生型而非磷酸化缺陷型 KCNQ2 可恢复这些作用。因此，D1R-ERK 信号通过 KCNQ2 磷酸化控制 MSN 兴奋性，从而调节奖励行为，使 KCNQ2 成为奖励回路功能障碍的精神疾病的潜在治疗靶点。
