Molecular Physiology Laboratory, Departamento de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
National Institute of Neurological Disorders and Stroke (NIH), Bethesda, MD, USA.
Sci Adv. 2020 Apr 1;6(14):eaay4472. doi: 10.1126/sciadv.aay4472. eCollection 2020 Apr.
The potassium channel Kv7.1 associates with the KCNE1 regulatory subunit to trigger cardiac currents. Although the Kv7.1/KCNE1 complex has received much attention, the subcellular compartment hosting the assembly is the subject of ongoing debate. Evidence suggests that the complex forms either earlier in the endoplasmic reticulum or directly at the plasma membrane. Kv7.1 and KCNE1 mutations, responsible for long QT syndromes, impair association and traffic, thereby altering currents. We found that Kv7.1 and KCNE1 do not assemble in the first stages of their biogenesis. Data support an unconventional secretory pathway for Kv7.1-KCNE1 that bypasses Golgi. This route targets channels to endoplasmic reticulum-plasma membrane junctions, where Kv7.1-KCNE1 assemble. This mechanism helps to resolve the ongoing controversy about the subcellular compartment hosting the association. Our results also provide new insights into channel localization at endoplasmic reticulum-plasma membrane junctions, highlighting an alternative anterograde trafficking mechanism for oligomeric ion channels.
钾通道 Kv7.1 与 KCNE1 调节亚基结合，引发心脏电流。尽管 Kv7.1/KCNE1 复合物受到了广泛关注，但组装所在的亚细胞隔室仍是一个正在讨论的话题。有证据表明，该复合物要么在早期的内质网中形成，要么直接在质膜上形成。负责长 QT 综合征的 Kv7.1 和 KCNE1 突变会损害其结合和运输，从而改变电流。我们发现 Kv7.1 和 KCNE1 不在其生物发生的早期阶段组装。数据支持 Kv7.1-KCNE1 的一种非常规分泌途径，该途径绕过高尔基体。这条途径将通道靶向内质网-质膜连接处，在那里组装 Kv7.1-KCNE1。这种机制有助于解决关于组装所在亚细胞隔室的持续争议。我们的结果还为内质网-质膜连接处通道定位提供了新的见解，突出了寡聚离子通道的另一种顺行运输机制。
