Impact of I Voltage and Ca/Mg-Dependent Rectification on Cardiac Repolarization.

Cardiac small conductance Ca-activated K (SK) channels are activated solely by Ca, but the SK current (I) is inwardly rectified. However, the impact of inward rectification in shaping action potentials (APs) in ventricular cardiomyocytes under β-adrenergic stimulation or in disease states remains undefined. Two processes underlie this inward rectification: an intrinsic rectification caused by an electrostatic energy barrier from positively charged amino acids at the inner pore and a voltage-dependent Ca/Mg block. Thus, Ca has a biphasic effect on I, activating at low [Ca] yet inhibiting I at high [Ca]. We examined the effect of I rectification on APs in rat cardiomyocytes by simultaneously recording whole-cell apamin-sensitive currents and Ca transients during an AP waveform and developed a computer model of SK channels with rectification features. The typical profile of I during AP clamp included an initial peak (mean 1.6 pA/pF) followed by decay to the point that submembrane [Ca] reached ∼10 μM. During the rest of the AP stimulus, I either plateaued or gradually increased as the cell repolarized and submembrane [Ca] decreased further. We used a six-state gating model combined with intrinsic and Ca/Mg-dependent rectification to simulate I and investigated the relative contributions of each type of rectification to AP shape. This SK channel model replicates key features of I recording during AP clamp showing that intrinsic rectification limits I at high V during the early and plateau phase of APs. Furthermore, the initial rise of Ca transients activates, but higher [Ca] blocks SK channels, yielding a transient outward-like I trajectory. During the decay phase of Ca, the Ca-dependent block is released, causing I to rise again and contribute to repolarization. Therefore, I is an important repolarizing current, and the rectification characteristics of an SK channel determine its impact on early, plateau, and repolarization phases of APs.