Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States.
School of Medicine, Virginia Polytechnic University, Roanoke, United States.
Elife. 2018 Aug 14;7:e37610. doi: 10.7554/eLife.37610.
Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) -mediated adhesion scaffolds -activating Na1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with Na1.5. Smart patch clamp (SPC) indicated greater sodium current density (I) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal I, but not whole cell I, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.
计算模型表明，心脏传导可能涉及电突触耦合 - 细胞间通讯，涉及电化学信号在心肌细胞之间的狭窄细胞外裂隙中传递。我们假设β1（SCN1B）介导的粘附支架 - 在紧邻缝隙连接（GJ）的狭窄（<30nm）perinexal 裂隙内激活 Na1.5（SCN5A）通道，促进电突触耦合。超分辨率成像表明β1优先定位于 perinexus，在那里它与 Na1.5 共定位。智能片上钳（SPC）表明，与非连接位点相比，perinexi 处的钠电流密度（I）更大。一种新型的、合理设计的肽βadp1 在电动细胞-基质阻抗传感研究中能够强烈且选择性地抑制β1介导的粘附。βadp1 显著加宽豚鼠心室中的 perinexi，并在心肌细胞单层中选择性地减少 perinexal I，但不减少整个细胞 I。在光学映射研究中，βadp1 引发心律失常性传导减慢。总之，β1 在 perinexus 处介导的粘附促进了心肌细胞之间的动作电位传播，可能代表一种新型的抗心律失常治疗靶点。
