The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

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 trans-activating NaV1.5 (SCN5A) channels within narrow (V1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) 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 INa, but not whol
e cell INa, 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-arr...

计算建模研究表明，心脏传导可能涉及ephaptic耦合（ephaptic coupling）——即通过心肌细胞间狭窄细胞外间隙传递电化学信号的细胞间通讯模式。我们提出假说：β1亚基（SCN1B）介导的黏附可作为支架，对狭窄连接旁间隙（perinexus，其复数形式为perinexi）内的NaV1.5（SCN5A）通道进行反式激活。智能膜片钳（Smart patch clamp, SPC）实验显示，相较于非连接位点，perinexus区域的钠电流密度（INa）更高。本研究研发了一种新型理性设计的肽类物质βadp1，在细胞-基质阻抗感应实验中，该物质可强效且选择性地抑制β1介导的黏附过程。在豚鼠心室组织中，βadp1可显著扩大perinexus区域；在心肌细胞单层培养物中，该物质可选择性降低perinexus区域的INa，但对全细胞INa无显著影响。光学标测实验结果显示，βadp1可诱发致心律失常性传导减慢。综上，perinexus处的β1介导黏附可促进心肌细胞间的动作电位传导，或可成为抗心律失常（原文截断）的新型靶点。