Effect Of Site Selective Ion Channel Blocking on Action Potential

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 mechanism such as (i) only sodium channel blocking, (ii) only potassium channel blocking and (iii) dual type blocking 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. Our results show that the nature of action potential termination process in presence of sodium and potassium channel blockers are distinct and physiologically very different from each other. We have found that although the sodium and potassium ionic currents have interdependent relationship over a course of an action potential but sodium and potassium 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 which are of great physiological and pharmacological importance. We have also shown how the ion channel blockers alter the gating dynamics and such altered gating itself modulates the ion channel blocking which opens the possibility of finding fundamental informations regarding probabilistic and dynamical features. Some experimental results of ion channel blocking in diverse systems have been validated through our site selected binding scheme. Many other types of blocking mechanisms such as closed state blocking, inactive state blocking etc can also be explored using our method with desired level of structural and functional details.