Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior
Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior
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DOI：
10.1016/j.celrep.2022.111309
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发表时间：
2022-09-06
期刊：
影响因子：
8.8
通讯作者：
Kaibuchi，Kozo
中科院分区：
文献类型：
--
作者：
Tsuboi，Daisuke;Otsuka，Takeshi;Kaibuchi，Kozo
多巴胺信号传导功能障碍与各种神经心理障碍有关。以前，我们报道，多巴胺增加D1受体（D1 R）表达的中型棘神经元（MSN）的兴奋性和放电率通过PKA/Rap 1/ERK途径，以促进奖励行为。在此，结果表明，D1 R激动剂SKF 81297抑制KCNQ介导的电流，并增加小鼠NAc切片中的D1 R-MSN放电率，这被ERK抑制所消除。在体外，ERK在Ser 414和Ser 476处磷酸化KCNQ 2;在体内，KCNQ 2在NAc切片中的多巴胺信号下游磷酸化。在D1 R-MSN中条件性删除Kcnq 2可降低SKF 81297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KCNQ 2可以恢复这些作用，但磷酸缺陷型KCNQ 2不能。因此，D1 R-ERK信号通过KCNQ 2磷酸化来控制MSN的兴奋性，以调节奖励行为，使KCNQ 2成为奖励回路功能失调的精神疾病的潜在治疗靶点。
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 vitroERK phosphorylates KCNQ2 at Ser414 and Ser476;in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion ofKcnq2in 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.