Manville Rían W, Sidlow Richard, Abbott Geoffrey W
Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Valley Children's Hospital, Department of Medical Genetics and Metabolism, Madera, CA, USA.
iScience. 2025 Aug 5;28(9):113283. doi: 10.1016/j.isci.2025.113283. eCollection 2025 Sep 19.
Sequence variants in , the gene encoding voltage-gated potassium channel Kv1.2, cause epilepsy, delayed cognitive development, and movement disorders. Drugs that directly correct mutant Kv1.2 function are lacking. Kv1.2 downregulation is also implicated in pain and amyotrophic lateral sclerosis (ALS). We recently found that the abietane diterpenoid pisiferic acid (PA) from conifer beneficially restores activity in pathogenic loss-of-function (LOF)-variant Kv1.1 channels. Here, using cellular electrophysiology, we classified 19 human Kv1.2 gene variants (pathogenic or of unknown significance) into LOF, gain of function (GOF), or mixed LOF/GOF. By hyperpolarizing their voltage dependence of activation, PA improved function in 13/13 LOF and 1/1 LOF/GOF pathogenic Kv1.2 variants tested, using cRNA ratios representative of autosomal dominant disorders. docking, mutagenesis, and electrophysiology identified a PA binding site in the Kv1.2 voltage sensor. Given its efficacy and low preclinical toxicity, PA is a promising lead compound for Kv1.2 LOF disorders.
编码电压门控钾通道Kv1.2的基因中的序列变异会导致癫痫、认知发育迟缓以及运动障碍。目前缺乏直接纠正突变型Kv1.2功能的药物。Kv1.2下调也与疼痛和肌萎缩侧索硬化症（ALS）有关。我们最近发现，来自针叶树的枞酸二萜类化合物枞酸（PA）能有益地恢复致病性功能丧失（LOF）变异的Kv1.1通道的活性。在这里，我们利用细胞电生理学方法，将19种人类Kv1.2基因变异（致病性或意义不明）分为LOF、功能获得（GOF）或混合LOF/GOF。通过超极化它们的激活电压依赖性，PA改善了13/13个LOF和1/1个LOF/GOF致病性Kv1.2变异体的功能，使用了代表常染色体显性疾病的cRNA比率。对接、诱变和电生理学确定了Kv1.2电压传感器中的一个PA结合位点。鉴于其有效性和较低的临床前毒性，PA是治疗Kv1.2 LOF疾病的一种有前景的先导化合物。
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