Role of SK Current Rectification in Shaping Action Potential of Ventricular Cardiomyocytes

Abstract

The role of cardiac small conductance Ca2+-activated K+ (SK) channels in shaping the action potential (AP) of ventricular cardiomyocytes remains undefined. Two processes underlie inward rectification of SK current (ISK), an intrinsic voltage-dependent rectification caused by positively charged amino acids at the inner pore, and a divalent ion block. The latter process gives Ca2+ a biphasic effect on ISK, activating at low [Ca2+] yet inhibiting ISK at high [Ca2+]. We examined the role of ISK rectification on AP in rat cardiomyocytes by simultaneously recording whole-cell apamin-sensitive currents and Ca2+ transients during an AP waveform, and developed a computer model of SK channel with rectification features. The typical profile of ISK during AP-clamp included an initial peak (mean 1.6 pA/pF) followed by decay to the point where submembrane [Ca2+] reached ∼10 μM. During the rest of the AP stimulus, ISK either plateaued or gradually increased as the cell repolarized and submembrane [Ca2+] continued to decrease. We used a six state gating model combined with intrinsic rectification and divalent block to simulate ISK and investigated the relative contributions of the two types of rectification to the AP shape. This SK channel model replicates key features of ISK recording during AP-clamp. The simulation shows that the rise of Ca2+ during Ca2+ transients activates SK channel opening, but higher [Ca2+] blocks channels, resulting in transient outward-like trajectory of ISK. During the decay phase of Ca2+, Ca2+-dependent block is released causing ISK to contribute to repolarization. The intrinsic rectification characteristics limit ISK during the early and plateau phase of APs to prevent excessive APD shortening. In conclusion, ISK is an important repolarizing current and the rectification characteristics of SK channel determines its impact on early, plateau and repolarization phases of APs.