Effect Of Site Selective Ion Channel Blocking on Action Potential

TL;DR

This study uses stochastic simulations to analyze how ion channel blockers affect action potential generation, revealing distinct physiological impacts and signatures for sodium and potassium channel blocking mechanisms.

Contribution

It extends the Hodgkin-Huxley model to incorporate drug blocking mechanisms, accurately reproducing experimental observations and elucidating the effects on ionic currents and gating dynamics.

Findings

Sodium channel blockers reduce action potential duration and decrease firing frequency.

Potassium channel blockers initially increase spiking activity before decreasing it.

Dual blockers cause non-monotonic changes in spiking frequency due to competing effects.

Abstract

In this work we have theoretically investigated how the action potential generation and its associated intrinsic properties are affected in presence of ion channel blockers by adapting Gillepie's stochastic simulation technique on a very basic neuron of Hodgkin-Huxley type. With a simple extension of the Hodgkin-Huxley Markov model we have mainly investigated three types of drug blocking mechanisms and showed that the major experimental and physiological observations such as ionic currents, spiking frequency trends, change in action potential shape and duration, altered gating dynamics etc due to the presence of ion channel blockers can be well reproduced. The nature of action potential termination process in presence of sodium and potassium channel blockers are distinct and physiologically very different from each other. Channel blockers have distinct signatures on ionic currents. In presence of only sodium channel blockers the frequency of action potential generation falls off exponentially with increasing drug affinity, whereas in contrast, for only potassium channel blockers initially an enhanced spiking activity of action potential is found followed by a gradual decrease of the spiking frequency as the drug affinity increases. In case of dual type blockers with equal sodium and potassium channel binding affinity, the spiking frequency passes through maxima and minima due to the competition between channel number fluctuation and overall sodium and potassium conductances. We have found that sodium channel blockers shorten the duration of action potential while the potassium channel blockers delay it. We have also shown how the ion channel blockers alter the gating dynamics. Some experimental results of ion channel blocking in diverse systems have been validated through our site selected binding scheme.