Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2)-deficient mice develop spontaneous seizures in early life because of a marked reduction in M currents, which regulate neuronal membrane excitability. We have previously shown that hyper-SUMOylation of the Kv7.2 and Kv7.3 channels is critically involved in the regulation of the M currents conducted by these potassium voltage-gated channels. Here, we show that hyper-SUMOylation of the Kv7.2 and Kv7.3 proteins reduced binding to the lipid secondary messenger PIP2. CaM1 has been shown to be tethered to the Kv7 subunits via hydrophobic motifs in its C termini and implicated in the channel assembly. Mutation of the SUMOylation sites on Kv7.2 and Kv7.3 specifically resulted in decreased binding to CaM1 and enhanced CaM1-mediated assembly of Kv7.2 and Kv7.3, whereas hyper-SUMOylation of Kv7.2 and Kv7.3 inhibited channel assembly. SENP2-deficient mice exhibited increased acetylcholine levels in the brain and the heart tissue because of increases in the vagal tone induced by recurrent seizures. The SENP2-deficient mice develop seizures followed by a period of sinus pauses or atrioventricular conduction blocks. Chronic administration of the parasympathetic blocker atropine or unilateral vagotomy significantly prolonged the life of the SENP2-deficient mice. Furthermore, we showed that retigabine, an M-current opener, reduced the transcription of SUMO-activating enzyme SAE1 and inhibited SUMOylation of the Kv7.2 and Kv7.3 channels, and also prolonged the life of SENP2-deficient mice. Taken together, the previously demonstrated roles of PIP2, CaM1, and retigabine on the regulation of Kv7.2 and Kv7.3 channel function can be explained by their roles in regulating SUMOylation of this critical potassium channel.

中文翻译：

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SUMO 特异性蛋白酶 SENP2 在 Kv7.2 和 Kv7.3 钾通道的调节中起重要作用。

Sentrin/小泛素样修饰剂 (SUMO) 特异性蛋白酶 2 (SENP2) 缺陷小鼠在生命早期会发生自发性癫痫，因为 M 电流显着减少，调节神经元膜兴奋性。我们之前已经表明，Kv7.2 和 Kv7.3 通道的超 SUMOylation 与这些钾电压门控通道传导的 M 电流的调节密切相关。在这里，我们显示 Kv7.2 和 Kv7.3 蛋白的超 SUMOylation 减少了与脂质二级信使 PIP2 的结合。CaM1 已被证明通过其 C 末端的疏水基序与 Kv7 亚基相连，并参与通道组装。Kv7.2 和 Kv7.3 上 SUMOylation 位点的突变特异性地导致与 CaM1 的结合降低并增强了 CaM1 介导的 Kv7.2 和 Kv7.3 组装，而 Kv7.2 和 Kv7.3 的超 SUMOylation 抑制了通道组装。由于反复发作引起的迷走神经张力增加，SENP2 缺陷小鼠的大脑和心脏组织中的乙酰胆碱水平增加。SENP2 缺陷小鼠出现癫痫发作，然后出现一段时间的窦性停顿或房室传导阻滞。副交感神经阻滞剂阿托品或单侧迷走神经切断术的长期给药显着延长了 SENP2 缺陷小鼠的寿命。此外，我们发现瑞替加滨（一种 M 电流开启剂）降低了 SUMO 激活酶 SAE1 的转录并抑制了 Kv7.2 和 Kv7.3 通道的 SUMO 化，并且还延长了 SENP2 缺陷小鼠的寿命。综上所述，先前证明的 PIP2、CaM1 和瑞替加滨对 Kv7.2 和 Kv7 的调节的作用。