Abstract
BACKGROUND: Small-conductance Ca(2+)-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca(2+) 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 Ca(2+) 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 Ca(2+) in the bulk cytosol, subsarcolemmal space, or junctional cleft. RESULTS: When SK channels sense Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) channels so that they preferentially sense Ca(2+) 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.