Potassium channels in the Cx43 gap junction perinexus modulate ephaptic coupling: an experimental and modeling study

Area of Science:

• Cardiovascular Physiology
• Cardiac Electrophysiology
• Cellular Biophysics

Background:

• Cardiac electrical excitation was traditionally attributed solely to gap junction (GJ) mediated ionic currents.
• Sodium channels (Nav1.5) at the perinexus were recently implicated in ephatic coupling, influencing cardiac conduction.
• Acute interstitial edema (AIE) impairs ephatic coupling, leading to conduction slowing and arrhythmias.

Purpose of the Study:

• To investigate the localization of Kir2.1 channels within the cardiac perinexus.
• To determine if inhibiting Kir2.1 channels can mitigate conduction abnormalities during AIE.
• To explore the role of Kir2.1 in ephatic coupling and cardiac arrhythmia.

Main Methods:

• Utilized super-resolution microscopy techniques: gated stimulated emission depletion (gSTED) and stochastic optical reconstruction microscopy (STORM).
• Performed experimental interventions involving Nav1.5 and Kir2.1 channel inhibition during AIE.
• Employed a nanodomain computer model to simulate and analyze intercellular coupling mechanisms.

Main Results:

• Confirmed significant localization of Kir2.1 channels within the perinexus alongside Nav1.5 channels.
• Demonstrated that Kir2.1 inhibition during AIE improved transverse conduction velocity and reduced arrhythmia risk compared to AIE alone.
• Showed that Nav1.5 inhibition during AIE exacerbated conduction slowing.

Conclusions:

• Kir2.1 channels are localized in the perinexus and modulate cardiac myocyte intercellular coupling and conduction anisotropy.
• Targeting Kir2.1 channels offers a potential therapeutic strategy to ameliorate AIE-induced arrhythmias.
• These findings challenge traditional views of cardiac excitation, highlighting the role of ephatic coupling involving ion channels.