AlRawashdeh Sara, Mosa Farag E S, Barakat Khaled H
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Front Mol Biosci. 2024 Aug 13;11:1341727. doi: 10.3389/fmolb.2024.1341727. eCollection 2024.
Cardiovascular diseases are a major global health concern, responsible for a significant number of deaths each year, often linked to cardiac arrhythmias resulting from dysfunction in ion channels. Hereditary Long QT Syndrome (LQTS) is a condition characterized by a prolonged QT interval on ECG, increasing the risk of sudden cardiac death. The most common type of LQTS, LQT2, is caused by mutations in the hERG gene, affecting a potassium ion channel. The majority of these mutations disrupt the channel's trafficking to the cell membrane, leading to intracellular retention. Specific high-affinity hERG blockers (e.g., E-4031) can rescue this mutant phenotype, but the exact mechanism is unknown. This study used accelerated molecular dynamics simulations to investigate how these mutations affect the hERG channel's structure, folding, endoplasmic reticulum (ER) retention, and trafficking. We reveal that these mutations induce structural changes in the channel, narrowing its central pore and altering the conformation of the intracellular domains. These changes expose internalization signals that contribute to ER retention and degradation of the mutant hERG channels. Moreover, the study found that the trafficking rescue drug E-4031 can inhibit these structural changes, potentially rescuing the mutant channels. This research offers valuable insights into the structural issues responsible for the degradation of rescuable transmembrane trafficking mutants. Understanding the defective trafficking structure of the hERG channel could help identify binding sites for small molecules capable of restoring proper folding and facilitating channel trafficking. This knowledge has the potential to lead to mechanism-based therapies that address the condition at the cellular level, which may prove more effective than treating clinical symptoms, ultimately offering hope for individuals with hereditary Long QT Syndrome.
心血管疾病是全球主要的健康问题，每年导致大量死亡，通常与离子通道功能障碍引起的心律失常有关。遗传性长QT综合征（LQTS）是一种心电图上QT间期延长的病症，增加了心源性猝死的风险。最常见的LQTS类型LQT2是由hERG基因突变引起的，该基因影响钾离子通道。这些突变中的大多数会破坏通道向细胞膜的转运，导致细胞内滞留。特定的高亲和力hERG阻滞剂（如E-4031）可以挽救这种突变表型，但其确切机制尚不清楚。本研究使用加速分子动力学模拟来研究这些突变如何影响hERG通道的结构、折叠、内质网（ER）滞留和转运。我们发现这些突变会引起通道的结构变化，使其中心孔变窄并改变细胞内结构域的构象。这些变化暴露了内化信号，这些信号导致突变型hERG通道的内质网滞留和降解。此外，研究发现转运挽救药物E-4031可以抑制这些结构变化，可能挽救突变通道。这项研究为可挽救的跨膜转运突变体降解的结构问题提供了有价值的见解。了解hERG通道有缺陷的转运结构有助于识别能够恢复正确折叠并促进通道转运的小分子结合位点。这一知识有可能带来基于机制的疗法，在细胞水平上解决该病症，这可能比治疗临床症状更有效，最终为遗传性长QT综合征患者带来希望。
