Autism-associated mutations in Kv7 channels induce gating pore current
Autism-associated mutations in Kv7 channels induce gating pore current
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DOI：
10.1073/pnas.2112666118
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发表时间：
2021-11-09
影响因子：
11.1
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
El-Din, Tamer M. Gamal;Lantin, Timothy;Catterall, William A.
自闭症谱系障碍（ASD）对美国超过1%的儿童产生不利影响，导致社会互动缺陷，重复行为和沟通障碍。通过基因组测序，ASD的遗传分析已经取得了显着进展，该基因组测序已经确定了ASD中具有突变的>500个基因。改变电压门控钾（K-v）通道K（v）7（KCNQ）电压传感器中精氨酸门控电荷的突变经常与ASD相关。我们假设这些门控电荷突变将通过引起通过突变电压传感器的离子泄漏来诱导门控孔电流（也称为Ω电流）。出乎意料的是，我们发现，野生型K（v）7通过其天然的电压传感器在正膜电位进行外向门控孔电流，由于谷氨酰胺在第三个门控电荷的位置。在细菌和人类K（v）7通道中，R1和R2位置的门控电荷突变导致在负膜电位下通过静息电压传感器的内向门控孔电流，而R4位置的突变导致在正电位下通过激活的电压传感器的外向门控孔电流。值得注意的是，K（v）7.3/R2 C ASD相关突变在小鼠中脑多巴胺神经元中的体内表达破坏了动作电位的产生和重复放电。总的来说，我们的研究结果揭示了K（v）7通道中的天然和突变门控孔电流，并暗示通过突变K（v）7通道门控孔电流作为自闭症的潜在致病机制来改变对动作电位产生的控制。
Autism spectrum disorder (ASD) adversely impacts >1% of children in the United States, causing social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis of ASD has advanced dramatically through genome sequencing, which has identified >500 genes with mutations in ASD. Mutations that alter arginine gating charges in the voltage sensor of the voltage-gated potassium (K-v) channel K(v)7 (KCNQ) are among those frequently associated with ASD. We hypothesized that these gating charge mutations would induce gating pore current (also termed omega-current) by causing an ionic leak through the mutant voltage sensor. Unexpectedly, we found that wild-type K(v)7 conducts outward gating pore current through its native voltage sensor at positive membrane potentials, owing to a glutamine in the third gating charge position. In bacterial and human K(v)7 channels, gating charge mutations at the R1 and R2 positions cause inward gating pore current through the resting voltage sensor at negative membrane potentials, whereas mutation at R4 causes outward gating pore current through the activated voltage sensor at positive potentials. Remarkably, expression of the K(v)7.3/R2C ASD-associated mutation in vivo in midbrain dopamine neurons of mice disrupts action potential generation and repetitive firing. Overall, our results reveal native and mutant gating pore current in K(v)7 channels and implicate altered control of action potential generation by gating pore current through mutant K(v)7 channels as a potential pathogenic mechanism in autism.