encodes the voltage-gated potassium channel K7.5, a member of the K7 channel family, which conducts the M-current. This current is a potent regulator of neuronal excitability by regulating membrane potential in the subthreshold range of action potentials and mediating the medium and slow afterhyperpolarization. Recently, we have identified five loss-of-function variants in in patients with genetic generalized epilepsy. Using the most severe dominant-negative variant (R359C), we set out to investigate pharmacological therapeutic intervention by K7 channel openers on channel function and neuronal firing. Retigabine and gabapentin increased R359C-derived M-current amplitudes in HEK cells expressing homomeric or heteromeric mutant K7.5 channels. Retigabine was most effective in restoring K currents. Ten μM retigabine was sufficient to reach the level of WT currents without retigabine, whereas 100 μM of gabapentin showed less than half of this effect and application of 50 μM ZnCl only significantly increased M-current amplitude in heteromeric channels. Overexpression of K7.5-WT potently inhibited neuronal firing by increasing the M-current, whereas R359C overexpression had the opposite effect and additionally decreased the medium afterhyperpolarization current. Both aforementioned drugs and Zn reversed the effect of R359C expression by reducing firing to nearly normal levels at high current injections. Our study shows that a dominant-negative variant with a complete loss-of-function in K7.5 leads to largely increased neuronal firing which may explain a neuronal hyperexcitability in patients. K7 channel openers, such as retigabine or gabapentin, could be treatment options for patients currently displaying pharmacoresistant epilepsy and carrying loss-of-function variants in .

中文翻译：

---

瑞替加滨和加巴喷丁在癫痫相关显性失活 KCNQ5 变体的细胞模型中恢复通道功能和神经元放电

编码电压门控钾通道 K7.5，它是 K7 通道家族的成员，传导 M 电流。该电流通过调节动作电位阈下范围内的膜电位并介导中度和慢速后超极化，是神经元兴奋性的有效调节剂。最近，我们在遗传性全面性癫痫患者中发现了五种功能丧失变异。使用最严重的显性失活变异（R359C），我们着手研究 K7 通道开放剂对通道功能和神经元放电的药物治疗干预。瑞替加滨和加巴喷丁增加了表达同聚或异聚突变 K7.5 通道的 HEK 细胞中 R359C 衍生的 M 电流幅度。瑞替加滨在恢复钾电流方面最有效。 10 μM 瑞替加滨足以达到没有瑞替加滨的 WT 电流水平，而 100 μM 加巴喷丁显示的效果不到一半，并且应用 50 μM ZnCl 仅显着增加异聚通道中的 M 电流幅度。 K7.5-WT 的过表达通过增加 M 电流来有效抑制神经元放电，而 R359C 过表达具有相反的效果，并且还降低了介质后超极化电流。上述两种药物和 Zn 通过在高电流注射时将放电降低至接近正常水平来逆转 R359C 表达的影响。我们的研究表明，K7.5 功能完全丧失的显性失活变异会导致神经元放电大幅增加，这可能解释了患者神经元过度兴奋的原因。 K7 通道开放剂，如瑞替加滨或加巴喷丁，可能是目前表现出耐药性癫痫和携带功能丧失变异的患者的治疗选择。