State-dependent inhibition of sodium channels by local anesthetics: A 40-year evolution

Wang, G. K.; Strichartz, Gary R.

doi:10.1134/s1990747812010151

Cited by 32 publications

(32 citation statements)

References 42 publications

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“…our results indicate that methyl eugenol has a higher affinity for inactivated and/or open channels, with weaker binding to channels in the resting state. Through its rapid binding to open channels and stabilization of a nonconducting state, methyl eugenol can produce greater and faster use-dependent inhibition of Na + current and slow the kinetics of recovery of channels in the inactivated state [40] . Methyl eugenol rapidly reaches a steady-state level in a use-dependent manner ( Figure 3B, 3C), similar to the usedependency evoked by lidocaine on Nav1.4 [41,42] , Nav1.7 [43,44] , Nav1.5 [45] , and Nav1.8 [43] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Inhibition of Nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions

et al. 2015

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“…The local anesthetic site is the most well studied site responsible for Nav and drug interaction. Also, a conserved phenylalanine (Phe) residue in the domain IV S6 segment appears to be most critical (Wang and Strichartz, 2012). To better understand Nav pharmacology, it is important to investigate whether Nav channels manifest promiscuous interaction with compounds and whether the Phe residue (F1760 in hNav1.5) is responsible for promiscuity.…”

Section: Resultsmentioning

confidence: 99%

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Zhang

Zou

et al. 2015

Molecular Pharmacology

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Voltage-gated sodium (Nav) channels are essential for membrane excitability and represent therapeutic targets for treating human diseases. Recent reports suggest that these channels, e.g., Nav1.3 and Nav1.5, are inhibited by multiple structurally distinctive small molecule drugs. These studies give reason to wonder whether these drugs collectively target a single site or multiple sites in manifesting such pharmacological promiscuity. We thus investigate the pharmacological profile of Nav1.5 through systemic analysis of its sensitivity to diverse compound collections. Here, we report a dual-color fluorescent method that exploits a customized Nav1.5 [calcium permeable Nav channel, subtype 5 (SoCal5)] with engineered-enhanced calcium permeability. SoCal5 retains wildtype (WT) Nav1.5 pharmacological profiles. WT SoCal5 and SoCal5 with the local anesthetics binding site mutated (F1760A) could be expressed in separate cells, each with a differentcolored genetically encoded calcium sensor, which allows a simultaneous report of compound activity and site dependence. The pharmacological profile of SoCal5 reveals a hit rate (.50% inhibition) of around 13% at 10 mM, comparable to that of hERG. The channel activity is susceptible to blockage by known drugs and structurally diverse compounds. The broad inhibition profile is highly dependent on the F1760 residue in the inner cavity, which is a residue conserved among all nine subtypes of Nav channels. Both promiscuity and dependence on F1760 seen in Nav1.5 were replicated in Nav1.4. Our evidence of a broad inhibition profile of Nav channels suggests a need to consider off-target effects on Nav channels. The site-dependent promiscuity forms a foundation to better understand Nav channels and compound interactions.

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“…4,31,32,33 Hille,34 in his modulated receptor hypothesis explains the shift of inactivation in presence of use-dependent block of sodium currents during repetitive pulses. 35,36,37 The hypothesis predicted that the open and inactivated states of voltage gated Na channels have higher affinities toward LA drugs than that of the resting state. The guardedreceptor model emphasizes the dependence of hydrophilic or hydrophobic path of the drug in binding and unbinding kinetics.…”

Section: Kinetics Of Drug Bindingmentioning

confidence: 99%

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

Pal

Gangopadhyay

2015

Channels

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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.

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State-dependent inhibition of sodium channels by local anesthetics: A 40-year evolution

Cited by 32 publications

References 42 publications

Inhibition of Nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions

Inhibition of Nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

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

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