β-adrenergic modulation of IKs gating in the guinea pig: What can be learned by numerical modelling

Mechanistic interpretation of ion channel function strictly based on experimental data is not always possible due to insurmontable technical difficulties. This is the case of native I
_Ks
, for which important aspects remain unresolved. This work aimed to test whether a structurally realistic scheme of IKs gating recently proposed by Silva and Rudy could account for I
_Ks
gating under baseline conditions and during beta-adrenergic stimulation. To this end, the Silva-Rudy model was optimized on a coherent set of experimental data concerning various aspects of IKs kinetics in control and during exposure to isoprenaline. The results obtained showed that the scheme proposed by Silva and Rudy is suitable to reproduce the full complexity of I
_Ks
gating both in baseline conditions and during beta-adrenergic stimulation. Analysis of model predictions disclosed a novel mechanism potentially accounting for a previously unresolved aspect of I
_Ks
modulation.