Exploring the Structure of the Voltage-gated Na+ Channel by an Engineered Drug Access Pathway to the Receptor Site for Local Anesthetics

Lukács, Péter; Gawali, Vaibhavkumar S.; Cervenka, René; Song, Ke; Koenig, Xaver; Rubi, Lena; Zarrabi, Touran; Hilber, Karlheinz; Stary-Weinzinger, Anna; Todt, Hannes

doi:10.1074/jbc.m113.541763

Cited by 7 publications

(11 citation statements)

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“…W1531G is located in the P-loop of DIV and is part of a highly conserved "ring of tryptophanes" forming a portion of the outer vestibule (Lipkind and Fozzard, 2000;Durell and Guy, 2001;Tikhonov and Zhorov, 2011). W1531G opens an external access/egress pathway for local anesthetics (Lukacs et al, 2014). The lidocaine-induced slow phase of recovery from short depolarizations was substantially accelerated in W1531G compared with wild-type channels, whereas lidocaine-modified recovery from inactivation produced by long depolarizations occurred at a much slower rate.…”

Section: Tablementioning

confidence: 97%

“…Such separation would be possible if a mutation would either accelerate recovery from lidocaine-modified I F or substantially slow recovery from native I M . We recently reported that mutation of a tryptophan in the outer vestibule of DIV produced a rapid access and egress pathway for external QX-222, a membrane impermeant derivative of lidocaine (Lukacs et al, 2014). As shown in Fig.…”

Section: Protocol Of Testing Time Course Of Recovery Frommentioning

confidence: 99%

“…11, C and D) most probably results from the drug-induced stabilization of I M , which prevents channels The mutation W1531G creates a pathway for rapid external drug access and egress (Lukacs et al, 2014), thereby allowing for assessment of gatingindependent drug dissociation. Here, we make use of this mutation to examine the contribution of drug-dissociation to the drug-induced prolongation of channel repriming.…”

Section: Tablementioning

confidence: 99%

“…Mutagenesis and electrophysiology were performed as reported (Zarrabi et al, 2010;Lukacs et al, 2014).…”

Section: Mutagenesis and Electrophysiologymentioning

confidence: 99%

“…In addition, we investigated the effect of lidocaine on recovery from inactivation in the mutation W1531G. This mutation has been shown to generate a pathway for rapid external access and egress of the permanently charged derivative of lidocaine QX-222 (Lukacs et al, 2014). This mutation can be used to study the effects of untrapping of drugs bound to the internal vestibule.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

et al. 2015

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The clinically important suppression of high-frequency discharges of excitable cells by local anesthetics (LA) is largely determined by drug-induced prolongation of the time course of repriming (recovery from inactivation) of voltage-gated Na 1 channels. This prolongation may result from periodic drugbinding to a high-affinity binding site during the action potentials and subsequent slow dissociation from the site between action potentials ("dissociation hypothesis"). For many drugs it has been suggested that the fast inactivated state represents the high-affinity binding state. Alternatively, LAs may bind with high affinity to a native slow-inactivated state, thereby accelerating the development of this state during action potentials ("stabilization hypothesis"). In this case, slow recovery between action potentials occurs from enhanced native slow inactivation. To test these two hypotheses we produced serial cysteine mutations of domain IV segment 6 in rNa v 1.4 that resulted in constructs with varying propensities to enter fast-and slowinactivated states. We tested the effect of the LA lidocaine on the time course of recovery from short and long depolarizing prepulses, which, under drug-free conditions, recruited mainly fast-and slow-inactivated states, respectively. Among the tested constructs the mutation-induced changes in native slow recovery induced by long depolarizations were not correlated with the respective lidocaine-induced slow recovery after short depolarizations. On the other hand, for long depolarizations the mutation-induced alterations in native slow recovery were significantly correlated with the kinetics of lidocaine-induced slow recovery. These results favor the "dissociation hypothesis" for short depolarizations but the "stabilization hypothesis" for long depolarizations.

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Section: Tablementioning

confidence: 97%

Section: Protocol Of Testing Time Course Of Recovery Frommentioning

confidence: 99%

Section: Tablementioning

confidence: 99%

“…Mutagenesis and electrophysiology were performed as reported (Zarrabi et al, 2010;Lukacs et al, 2014).…”

Section: Mutagenesis and Electrophysiologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

et al. 2015

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Mechanism of Inactivation in Voltage-Gated Na+ Channels

Gawali

Todt

2016

Na Channels From Phyla to Function

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Voltage-gated sodium channels

Kwong¹,

Carr²

2015

Current Opinion in Pharmacology

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Exploring the Structure of the Voltage-gated Na+ Channel by an Engineered Drug Access Pathway to the Receptor Site for Local Anesthetics

Cited by 7 publications

References 57 publications

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

Mechanism of Inactivation in Voltage-Gated Na+ Channels

Voltage-gated sodium channels

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Exploring the Structure of the Voltage-gated Na+ Channel by an Engineered Drug Access Pathway to the Receptor Site for Local Anesthetics

Cited by 7 publications

References 57 publications

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na+ Channels

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na+ Channels

Mechanism of Inactivation in Voltage-Gated Na+ Channels

Voltage-gated sodium channels

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Product

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Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels