Termination of Action Potential Due to Site Selective Ion Channel Blockers

Here, we have provided a qualitative theoretical description about how the action potential generation and its associated intrinsic properties such as ionic current, spiking frequency, action potential duration, gating dynamics, etc. are affected due to site selective ion channel blockers, by suitably adapting Gillespie’s stochastic simulation technique to an extended Hodgkin–Huxley Markov model, representing a very basic type of neuron. Considering different types and degrees of blocking potency of channel blockers to channel proteins, we have found that the nature of action potential termination process and corresponding ionic current profiles are very distinct from each other. With the increasing blocking affinity, the frequency of action potential spiking falls off exponentially in presence of sodium channel only blockers and dual type blockers having more sodium binding potency than potassium blockers, whereas in contrast, for potassium channel only blockers, dual type blockers having equal or higher potassium blocking affinity with respect to sodium blocking, the spiking frequency initially is enhanced followed by a gradual decrease due to the competition between channel number fluctuation and overall sodium and potassium conductances. Sodium channel blockers tend to shorten the action potential duration while the potassium channel blockers broaden it. The channel gating dynamics are also found to be changed drastically for different types of blockers. The final quiescent state arrival time and the quiescent state membrane voltage profiles show distinct features for different types of channel blockers with different applied external stimulus. Finally, we showed how consistent our results are with the existing literature of experimentally observed channel blocking effects in diverse systems and compared the similarities, dissimilarities and advantages of our model with an existing theoretical drug binding model with Langevin description. Our approach provides a qualitative pathway to investigate the effects of many other types of blocking mechanisms such as closed state, inactivated state blocking with desired level of structural and functional details.