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

Abstract

Inactivation path of voltage gated sodium channel has been studied here under various voltage protocols as it is the main governing factor for the periodic occurrence and shape of the action potential. These voltage protocols actually serve as non-equilibrium response spectroscopic tools to study the ion channel in non-equilibrium environment. In contrast to a lot of effort in finding the crystal structure based molecular mechanism of closed-state(CSI) and open-state inactivation(OSI); here our approach is to understand the dynamical characterization of inactivation. The kinetic flux as well as energetic contribution of the closed and open- state inactivation path is compared here for voltage protocols, namely constant, pulsed and oscillating. The non-equilibrium thermodynamic quantities used in response to these voltage protocols serve as improved characterization tools for theoretical understanding which not only agrees with the previously known kinetic measurements but also predict the energetically optimum processes to sustain the auto-regulatory mechanism of action potential and the consequent inactivation steps needed. The time dependent voltage pattern governs the population of the conformational states which when couple with characteristic rate parameters, the CSI and OSI selectivity arise dynamically to control the inactivation path. Using constant, pulsed and continuous oscillating voltage protocols we have shown that during depolarization the OSI path is more favored path of inactivation however, in the hyper-polarized situation the CSI is favored. It is also shown that the re-factorisation of inactivated sodium channel to resting state occurs via CSI path. Here we have shown how the subtle energetic and entropic cost due to the change in the depolarization magnitude determines the optimum path of inactivation. It is shown that an efficient CSI and OSI dynamical profile in principle can characterize the open-state drug blocking phenomena.

Kilohertz waveforms optimized to produce closed-state Na+ channel inactivation eliminate onset response in nerve conduction block

“…The HH-type models represent an ionic channel as an assembly of several independent gating particles, which are not sufficient to capture specific kinetics of VGSCs [47,48]. Unlike the HH formalism, Markov-type models represent an ion channel as a series of conformational states of the channel protein and a collection of transitions between them [18,22], which allowed us to reproduce the dependence of Na + inactivation on activation. We used Markov-type kinetic models of VGSCs to design the transmembrane voltage trajectory for causing Na + CSI.…”

“…However, recordings in cardiac cells [20,23,24], skeletal muscle [25], neuroblastoma cells [19,26], squid giant axon [21], medullary raphe neurons [27], and dorsal root ganglion neurons [28,29] confirm that VGSCs can also inactivate from pre-open closed states without first opening, called closed-state inactivation (CSI). This path occurs at hyperpolarized and modestly depolarized potentials without generation of an AP [18,22,24,26]. Based on these findings, we hypothesized that moving VGSCs into CSI without first causing activation would eliminate the initiation of APs and thus prevent the onset response.…”

“…Membrane depolarization also causes inactivation of VGSCs, which prevents Na + influx and facilitates repolarization to the resting potential. Na + inactivation is coupled to activation [18][19][20], and typically occurs from the open state at strongly depolarized membrane potentials [21,22], also called open-state inactivation (OSI). However, recordings in cardiac cells [20,23,24], skeletal muscle [25], neuroblastoma cells [19,26], squid giant axon [21], medullary raphe neurons [27], and dorsal root ganglion neurons [28,29] confirm that VGSCs can also inactivate from pre-open closed states without first opening, called closed-state inactivation (CSI).…”

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.…”