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

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Abstract
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 whole 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-arrhythmic therapies.
Funding Information
  • National Heart, Lung, and Blood Institute (RO1 HL56728-15A2)
  • American Heart Association (16SDG29870007)
  • National Heart, Lung, and Blood Institute (R01 HL102298-01A1)
  • National Institutes of Health (R01 HL102298-01A1)
  • National Institutes of Health (R37NS076752)
  • National Heart, Lung, and Blood Institute (RO1 HL HL141855-01)

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