UCLA

Background

Small-conductance Ca²⁺-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca²⁺ channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown.

Objective

The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca²⁺ channels in promoting J-wave syndrome and ventricular arrhythmias.

Methods

We carried out computer simulations of single-cell and tissue models. SK channels in the model were assigned to preferentially sense Ca²⁺ in the bulk cytosol, subsarcolemmal space, or junctional cleft.

Results

When SK channels sense Ca²⁺ in the bulk cytosol, the SK current (I_SK) rises and decays slowly during an action potential, the action potential duration (APD) decreases as the maximum conductance increases, no complex APD dynamics and phase 2 reentry can be induced by I_SK. When SK channels sense Ca²⁺ in the subsarcolemmal space or junctional cleft, I_SK can rise and decay rapidly during an action potential in a spike-like pattern because of spiky Ca²⁺ transients in these compartments, which can cause spike-and-dome action potential morphology, APD alternans, J-wave elevation, and phase 2 reentry. Our results can account for the experimental finding that activation of I_SK induced J-wave syndrome and phase 2 reentry in rabbit hearts.

Conclusion

Colocalization of SK channels with L-type Ca²⁺ channels so that they preferentially sense Ca²⁺ in the subsarcolemmal or junctional space may result in a spiky I_SK, which can functionally play a similar role of the transient outward K⁺ current in promoting J-wave syndrome and ventricular arrhythmias.