Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

Abstract

The kinetics and nonequilibrium thermodynamics of open state and inactive state drug binding mechanisms have been studied here using different voltage protocols in sodium ion channel. We have found that for constant voltage protocol, open state block is more efficient in blocking ionic current than inactive state block. Kinetic effect comes through peak current for mexiletine as an open state blocker and in the tail part for lidocaine as an inactive state blocker. Although the inactivation of sodium channel is a free energy driven process, however, the two different kinds of drug affect the inactivation process in a different way as seen from thermodynamic analysis. In presence of open state drug block, the process initially for a long time remains entropy driven and then becomes free energy driven. However in presence of inactive state block, the process remains entirely entropy driven until the equilibrium is attained. For oscillating voltage protocol, the inactive state blocking is more efficient in damping the oscillation of ionic current. From the pulse train analysis it is found that inactive state blocking is less effective in restoring normal repolarisation and blocks peak ionic current. Pulse train protocol also shows that all the inactive states behave differently as one inactive state responds instantly to the test pulse in an opposite manner from the other two states.

Veratridine modifies the gating of human voltage-gated sodium channel Nav1.7

“…6), suggesting that veratridine could also bind to Nav1.7 in the inactivated state to inhibit its peak current. A similar effect has been shown for other Na + blockers such as lidocaine (for Nav1.7) and carvacrol (for the TTX-R sodium current), which are suggested to bind to the inactivated state of the channel [50][51][52]. In conclusion, our study showed that veratridine exhibited a dose-dependent and use-dependent inhibitory effect on the peak current of Nav1.7 and shifted the activation curve and steady-state inactivation curve of Nav1.7 in the hyperpolarized direction, while enhancing the sustained current and tail current, which could contribute to the associated Na + influx.…”

Dynamical characterization of inactivation path in voltage-gated Na+ion channel by non-equilibrium response spectroscopy

“…30 Beside all these although a great deal of effort has been exercised to kinetically understand the molecular mechanism of inactivation, the nonequilibrium thermodynamics in the problems of inactivation has never been applied. The study of nonequilibrium parameters like total entropy production rates can be used to confirm the kinetic results 32 For oscillating voltage protocol, with its biophysically chosen amplitude, frequency and mean voltage, the system replicates the neuronal oscillation which arises due to oscillatory nature of the membrane depolarization. Also the pulse train protocol is applied here which activates and then deactivates the channel providing a scope to study the path of activation and then the recovery path from inactivation to resting state during refractory period.…”

“…[51][52][53][54][55] In this section we have investigated the effect of drug in the path of inactivation. We have taken a popular example of an open-state drug blocker, Mexilitine 32,55 which mainly attaches to the open-state of the channel and restricts the flow of ions through the channel into the cell. Thus here we add an extra state P M 5 with P 5 for the study of Mexiletine drug binding kinetics 32 as seen from Figure 13.…”

“…We have taken a popular example of an open-state drug blocker, Mexilitine 32,55 which mainly attaches to the open-state of the channel and restricts the flow of ions through the channel into the cell. Thus here we add an extra state P M 5 with P 5 for the study of Mexiletine drug binding kinetics 32 as seen from Figure 13. The model is given in Figure 11 Although this sort of theoretical model oriented studies have limitations 57,58 but it is also true that they can act as useful tools in guiding experimentation 59,60 and may suggest novel directions in studying inactivation.…”

Effect of Channel Noise in Synchronization and Metabolic Energy Consumption in Unidirectionally Coupled Neurons: Drug Blocking of Sodium and Potassium Channels

“…tetrodotoxin (TTX), second one is potassium blockers, e.g. tetraethylammonium (TEA) and the third type is total blockers [35][36][37]. These drugs selectively blocks either sodium or potassium channels and thus the available number of channels left for ion conduction gets reduced.…”