|Authors||I. G. M. van Herck, B. H. Bentzen, V. Seutin, J. Koivumäki, M. Maleckar, N. V. Marrion and A. G. Edwards|
|Title||In silico Model of Gating Kinetics, Temperature Dependence and Calcium Sensitivity of the SK Channel|
|Project(s)||AFib-TrainNet: EU Training Network on Novel Targets and Methods in Atrial Fibrillation|
|Year of Publication||2018|
|Place Published||Biophysical Society Thematic Meeting: The Heart by Numbers|
|Type of Work||Conference Poster|
The small conductance calcium activated potassium (SK) channel affects atrial repolarization and is implicated in the onset and progression of atrial fibrillation (AF). In vitro, in vivo and genetic studies have provided functional and molecular links between SK channels and AF. SK inhibition promotes AF termination and protects against AF re-induction in large animal models, but the effect of SK modulation in humans remains limited and controversial.
Objective: To provide a detailed computational SK model for interrogating the role of these channels in human atrial electrophysiology and arrhythmogenesis.
Methods and Results: We have constructed a detailed Markov SK model from single channel and excised inside-out macropatch recordings. Single channel data confirmed the previously reported gating structure of neuronal SK2 channels (4 closed and 2 open states), and were used to define the transition kinetics for calcium-dependent SK activation. Inside-out macropatch recordings uncovered a strong temperature-dependence of SK Ca2+-sensitivity. At room temperature, the EC50 for hSK2 and hSK3 was 0.38 ± 0.02 µM and 0.53 ± 0.07 µM, respectively. Increasing the temperature to 37°C shifted SK Ca2+-sensitivity towards the diastolic range for both hSK2 and hSK3 (EC50 = 0.22 ± 0.01 µM and 0.18 ± 0.02 µM, respectively). The associated Q10 values were 1.44 (hSK2) and 2.05 (hSK3). This temperature dependence will be incorporated into the Markovian formulation, which itself will be embedded in a human atrial myocyte model and tissue constructs, to assess the implications for SK channel function in vivo.
Conclusions: The novel temperature dependence of SK channel Ca2+-sensitivity indicates partial channel activity during atrial diastole. This finding implies that SK channel localization may be less important than previously assumed, and that SK channels may be capable of modulating atrial resting potential and repolarization, particularly during calcium overload and AF.