Impact of ISK Voltage and Ca2+/Mg2+-Dependent Rectification on Cardiac Repolarization

Abstract

Cardiac small conductance Ca 2þ -activated K þ (SK) channels are activated solely by Ca 2þ , but the SK current (I SK ) is inwardly rectified. However, the impact of inward rectification in shaping action potentials (APs) in ventricular cardiomyocytes under b-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 2þ /Mg 2þ block. Thus, Ca 2þ has a biphasic effect on I SK , activating at low [Ca 2þ ] yet inhibiting I SK at high [Ca 2þ ]. We examined the effect of I SK rectification on APs in rat cardiomyocytes by simultaneously recording whole-cell apamin-sensitive currents and Ca 2þ transients during an AP waveform and developed a computer model of SK channels with rectification features. The typical profile of I SK during AP clamp included an initial peak (mean 1.6 pA/pF) followed by decay to the point that submembrane [Ca 2þ ] reached $10 mM. During the rest of the AP stimulus, I SK either plateaued or gradually increased as the cell repolarized and submembrane [Ca 2þ ] decreased further. We used a six-state gating model combined with intrinsic and Ca 2þ /Mg 2þ -dependent rectification to simulate I SK and investigated the relative contributions of each type of rectification to AP shape. This SK channel model replicates key features of I SK recording during AP clamp showing that intrinsic rectification limits I SK at high V m during the early and plateau phase of APs. Furthermore, the initial rise of Ca 2þ transients activates, but higher [Ca 2þ ] blocks SK channels, yielding a transient outward-like I SK trajectory. During the decay phase of Ca 2þ , the Ca 2þ -dependent block is released, causing I SK to rise again and contribute to repolarization. Therefore, I SK is an important repolarizing current, and the rectification characteristics of an SK channel determine its impact on early, plateau, and repolarization phases of APs.

Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms

“…These channels activate and allow hyperpolarizing outward current when [Ca 2+ ] myo is elevated with a K 0.5 = 0.5 µM [72]. The SK channel conductance in rat peaks at 1-2 pA/pF [73]. This Ca 2+ sensitivity is conferred though the binding of Ca 2+ with calmodulin with experimental studies suggesting calmodulin variants can alter SK channel function and potentially lead to arrhythmia [74].…”

“…Furthermore, SK channel expression has been observed to increase during heart failure or after myocardial infarction and have been suggested to contribute to arrhythmia [75,76]. Computational rabbit ventricular myocyte models have suggested that when these channels are blocked, a mild to moderate action potential prolongation occurs depending on the conductance level assigned to the channel [73,76]. However, at the physiological conductance levels, these models predict a very small effect.…”

Does the small conductance Ca2+-activated K+ current ISK flow under physiological conditions in rabbit and human atrial isolated cardiomyocytes?

“…Furthermore, chronic hyper-adrenergic drive (e.g. associated with ventricular hypertrophy [50]) may enhance I SK , by PKA-dependent phosphorylation and altered channel rectification [50,52]. Neither acute nor chronic adrenergic activation were studied here, but their complex signalling pathways, potentially involving a wide range of I SK -associated multi-protein complexes (e.g.…”

An in Silico Investigation into the Role of SK Channels in Failing Ventricular Myocytes

“…To do so, a formulation without rectification was chosen for I SK . Alternative formulations with rectification, as in [12], would require the estimation of a larger number of parameters, which, given the lack of sufficient experimental data, could introduce a high degree of uncertainty in the model. In our selected formulation, the values for the time constants and the dissociation constant were taken from the literature.…”