Models of potassium channel inactivation: implications for open channel block

Inactivation is a widespread property of voltage-gated ion channels. Recent molecular biological advances in the potassium channel field have elucidated two mechanistically distinct types of inactivation, N-type and C-type. Both of these mechanisms are partially coupled to activation and are usually voltage insensitive once activation is complete. This study compared the effects of a hypothetical open channel blocker on macroscopic currents by using two different models of the same cardiac transient outward current channel. Model 1 is a Hodgkin-Huxley-like model in which inactivation is an independent voltage-sensitive process. Model 2 is a model in which inactivation is voltage insensitive but is partially coupled to activation. Both models have been shown to reproduce closely the experimentally observed current. However, when modelling open channel block, the two models can differ substantially in their equilibrium degree of drug binding. This difference in equilibrium can make substantial changes in the rate of current recovery in subsequent depolarizations. It is shown that, for a rapid series of depolarizations, the time course of development of block and the degree of steady state block can differ substantially between the two models. In conclusion, molecular mechanisms of inactivation must be taken into account when modelling conformation-specific drug binding and use dependence.