Molecular Determinants of Voltage-dependent Gating and Binding of Pore-blocking Drugs in Transmembrane Segment IIIS6 of the Na+ Channel α Subunit

Yarov‐Yarovoy, Vladimir; Brown, Jacob L.; Sharp, Elizabeth M.; Clare, Jeffrey J.; Scheuer, Todd; Catterall, William A.

doi:10.1074/jbc.m006992200

Cited by 229 publications

(219 citation statements)

References 42 publications

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“…[47][48][49][50] The different clinical actions of the drugs can be explained in terms of specific effects on channel function. AEDs that modulate voltage-dependent Na ϩ channels produce a voltage-and use-dependent block of the channels by binding predominantly to the inactivated state of the channels, thus suppressing high-frequency, repetitive action potential firing.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

“…The binding of phenytoin and the frequencydependent block of Na ϩ current was diminished by mutations F1764A and Y1771A in transmembrane segment IVS6. 47,48 Further studies with lamotrigine and some related compounds revealed that the nearby I1760 and additional residues in IIIS6 are also critical to drug binding 49,50,61 (FIG. 1).…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

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Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…, where h is the fraction of inactivated channels in control, and I D is the fraction of channels blocked at the drug concentration [D] (Kuo and Bean, 1994;Yarov-Yarovoy et al, 2001). The holding potential of −90 mV was used for BgNa v 1-4, and −60 mV for both BgNa v 1-1 and BgNa v 1-4 E1689K channels.…”

Section: K1689e Is Responsible For the Differences In Voltage-dependementioning

confidence: 99%

Molecular basis of differential sensitivity of insect sodium channels to DCJW, a bioactive metabolite of the oxadiazine insecticide indoxacarb

2006

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Indoxacarb (DPX-JW062) was recently developed as a new oxadiazine insecticide with high insecticidal activity and low mammalian toxicity. Previous studies showed that indoxacarb and its bioactive metabolite, N-decarbomethoxyllated JW062 (DCJW), block insect sodium channels in nerve preparations and isolated neurons. However, the molecular mechanism of indoxacarb/DCJW action on insect sodium channels is not well understood. In this study, we identified two cockroach sodium channel variants, BgNa v 1-1 and BgNa v 1-4, which differ in voltage dependence of fast and slow inactivation, and channel sensitivity to DCJW. The voltage dependence of fast inactivation and slow inactivation of BgNa v 1-4 were shifted in the hyperpolarizing direction compared with those of BgNa v 1-1 channels. At the holding potential of −90 mV, 20 μM of DCJW reduced the peak current of BgNa v 1-4 by about 40%, but had no effect on BgNa v 1-1. However, at the holding potential of −60 mV, DCJW also reduced the peak currents of BgNa v 1-1 by about 50%. Furthermore, DCJW delayed the recovery from slow inactivation of both variants. Substitution of E1689 in segment 4 of domain four (IVS4) of BgNa v 1-4 with a K, which is present in BgNa v 1-1, was sufficient to shift the voltage dependence of fast and slow inactivation of BgNa v 1-4 channels to the more depolarizing membrane potential close to that of BgNa v 1-1 channels. The E1689K change also eliminated the DCJW inhibition of BgNa v 1-4 at the hyperpolarizing holding potentials. These results show that the E1689K change is responsible for the difference in channel gating and sensitivity to DCJW between BgNa v 1-4 and BgNa v 1-1. Our results support the notion that DCJW preferably acts on the inactivated state of the sodium channel and demonstrate that K1689E is a major molecular determinant of the voltage-dependent inactivation and state-dependent action of DCJW.

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“…In addition, more recently, some residues arising from DIII-S6 and DI-S6 have also been shown to be the local anaesthetic binding sites. Yarov-Yarovoy et al (2001) showed that mutations L1465A, N1466A, and I1469A in the segment DIII-S6 of the rat brain type IIA sodium channel decreased the affinity of the inactivated sodium channels for etidocaine. Lysine mutations of rat skeletal muscle m1 sodium channel S1276 and L1280 (homologous to L1465 in the rat brain type IIA channel) in the segment DIII-S6 reduced the inactivated state affinity for bupivacaine (Wang et al, 2000).…”

Section: Hirose Et Al Kifmk Suppresses Insulin Signalling 225mentioning

confidence: 99%

“…No residues in IR structure are elucidated as important determinants for binding lignocaine. In sodium channels, some residues of the segments 6 of domains IV (DIV-S6), III (DIII-S6), and I (DI-S6), but not of domain II (DII-S6), are considered to be forming local anaesthetic binding sites (Ragsdale et al, 1994;Nau et al, 1999;Wang et al, 2000;Yarov-Yarovoy et al, 2001). Kuroda et al (1996; studied the interactions between local anaesthetics and sodium channel inactivation gaterelated peptides (G1484 -K1495; Figure 1), which are dissected from the III -IV linker connecting DIII-S6 and DIV-S1 of rat brain type IIA sodium channel.…”

Section: Introductionmentioning

confidence: 99%

Suppression of insulin signalling by a synthetic peptide KIFMK suggests the cytoplasmic linker between DIII‐S6 and DIV‐S1 as a local anaesthetic binding site on the sodium channel

Hirose¹,

Kuroda²,

Sawa³

et al. 2004

British J Pharmacology

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1 Acetyl-KIFMK-amide (KIFMK) restores fast inactivation to mutant sodium channels having a defective inactivation gate. Its binding site with sodium channels could be considered to be the cytoplasmic linker (III -IV linker) connecting domains III and IV of the sodium channel a subunit. There is a close resemblance of the amino-acid sequences between the III -IV linker and the activation loop of the insulin receptor (IR). This resemblance of the amino-acid sequences suggests that KIFMK may also modulate insulin signalling. In order to test this assumption, we studied the effects of KIFMK and its related (KIYEK, KIQMK, and DIYET) and unrelated (LPFFD) peptides on tyrosine phosphorylation or dephosphorylation of IR in vitro. 2 Purified IR was phosphorylated in vitro with insulin in the presence of various synthetic peptides and lignocaine. The phosphorylation level of IR was then evaluated after SDS -PAGE separation, followed by Western blot analysis with antiphosphotyrosine antibody. 3 KIFMK and KIYEK inhibited insulin-stimulated autophosphorylation of IR. Lignocaine showed similar effects, but at a higher order of concentration. KIYEK and DIYET, but not KIFMK, dephosphorylated the phosphorylated tyrosine residues. The structurally unrelated peptide LPFFD had no effect either on phosphorylation or dephosphorylation of IR. 4 These results indicate that KIFMK, KIYEK, and lignocaine bind with the autophosphorylation sites of IR. 5 The present findings also suggest that KIFMK and lignocaine bind with the III -IV linker of sodium channel a subunit.

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Molecular Determinants of Voltage-dependent Gating and Binding of Pore-blocking Drugs in Transmembrane Segment IIIS6 of the Na+ Channel α Subunit

Cited by 229 publications

References 42 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Molecular basis of differential sensitivity of insect sodium channels to DCJW, a bioactive metabolite of the oxadiazine insecticide indoxacarb

Suppression of insulin signalling by a synthetic peptide KIFMK suggests the cytoplasmic linker between DIII‐S6 and DIV‐S1 as a local anaesthetic binding site on the sodium channel

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