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J Biol Chem
2011 Oct 07;28640:35209-17. doi: 10.1074/jbc.M111.259507.
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Elucidation of the molecular basis of selective recognition uncovers the interaction site for the core domain of scorpion alpha-toxins on sodium channels.
Gur M
,
Kahn R
,
Karbat I
,
Regev N
,
Wang J
,
Catterall WA
,
Gordon D
,
Gurevitz M
.
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Neurotoxin receptor site-3 at voltage-gated Na(+) channels is recognized by various peptide toxin inhibitors of channel inactivation. Despite extensive studies of the effects of these toxins, their mode of interaction with the channel remained to be described at the molecular level. To identify channel constituents that interact with the toxins, we exploited the opposing preferences of LqhαIT and Lqh2 scorpion α-toxins for insect and mammalian brain Na(+) channels. Construction of the DIV/S1-S2, DIV/S3-S4, DI/S5-SS1, and DI/SS2-S6 external loops of the rat brain rNa(v)1.2a channel (highly sensitive to Lqh2) in the background of the Drosophila DmNa(v)1 channel (highly sensitive to LqhαIT), and examination of toxin activity on the channel chimera expressed in Xenopus oocytes revealed a substantial decrease in LqhαIT effect, whereas Lqh2 was as effective as at rNa(v)1.2a. Further substitutions of individual loops and specific residues followed by examination of gain or loss in Lqh2 and LqhαIT activities highlighted the importance of DI/S5-S6 (pore module) and the C-terminal region of DIV/S3 (gating module) of rNa(v)1.2a for Lqh2 action and selectivity. In contrast, a single substitution of Glu-1613 to Asp at DIV/S3-S4 converted rNa(v)1.2a to high sensitivity toward LqhαIT. Comparison of depolarization-driven dissociation of Lqh2 and mutant derivatives off their binding site at rNa(v)1.2a mutant channels has suggested that the toxin core domain interacts with the gating module of DIV. These results constitute the first step in better understanding of the way scorpion α-toxins interact with voltage-gated Na(+)-channels at the molecular level.
Bosmans,
Deconstructing voltage sensor function and pharmacology in sodium channels.
2008, Pubmed,
Xenbase
Bosmans,
Deconstructing voltage sensor function and pharmacology in sodium channels.
2008,
Pubmed
,
Xenbase
Campos,
Alpha-scorpion toxin impairs a conformational change that leads to fast inactivation of muscle sodium channels.
2008,
Pubmed
,
Xenbase
Catterall,
Binding of scorpion toxin to receptor sites associated with sodium channels in frog muscle. Correlation of voltage-dependent binding with activation.
1979,
Pubmed
Catterall,
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.
2000,
Pubmed
Cestèle,
Structure and function of the voltage sensor of sodium channels probed by a beta-scorpion toxin.
2006,
Pubmed
Cestèle,
Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.
2000,
Pubmed
Chen,
Interaction of scorpion alpha-toxins with cardiac sodium channels: binding properties and enhancement of slow inactivation.
2001,
Pubmed
Chen,
Modulation of cloned skeletal muscle sodium channels by the scorpion toxins Lqh II, Lqh III, and Lqh alphaIT.
2000,
Pubmed
Derst,
Four novel sequences in Drosophila melanogaster homologous to the auxiliary Para sodium channel subunit TipE.
2006,
Pubmed
,
Xenbase
Featherstone,
Interaction between fast and slow inactivation in Skm1 sodium channels.
1996,
Pubmed
,
Xenbase
Feng,
Cloning and functional analysis of TipE, a novel membrane protein that enhances Drosophila para sodium channel function.
1995,
Pubmed
,
Xenbase
Gilles,
Variations in receptor site-3 on rat brain and insect sodium channels highlighted by binding of a funnel-web spider delta-atracotoxin.
2002,
Pubmed
Gilles,
Effect of depolarization on binding kinetics of scorpion alpha-toxin highlights conformational changes of rat brain sodium channels.
2001,
Pubmed
Goldin,
Mechanisms of sodium channel inactivation.
2003,
Pubmed
Gordon,
The differential preference of scorpion alpha-toxins for insect or mammalian sodium channels: implications for improved insect control.
2007,
Pubmed
Kahn,
Molecular requirements for recognition of brain voltage-gated sodium channels by scorpion alpha-toxins.
2009,
Pubmed
,
Xenbase
Karbat,
The unique pharmacology of the scorpion alpha-like toxin Lqh3 is associated with its flexible C-tail.
2007,
Pubmed
Karbat,
Molecular basis of the high insecticidal potency of scorpion alpha-toxins.
2004,
Pubmed
Leipold,
Molecular interaction of delta-conotoxins with voltage-gated sodium channels.
2005,
Pubmed
Leipold,
Combinatorial interaction of scorpion toxins Lqh-2, Lqh-3, and LqhalphaIT with sodium channel receptor sites-3.
2004,
Pubmed
Liu,
Molecular basis of the mammalian potency of the scorpion alpha-like toxin, BmK M1.
2005,
Pubmed
,
Xenbase
Moran,
Molecular analysis of the sea anemone toxin Av3 reveals selectivity to insects and demonstrates the heterogeneity of receptor site-3 on voltage-gated Na+ channels.
2007,
Pubmed
,
Xenbase
Pathak,
Closing in on the resting state of the Shaker K(+) channel.
2007,
Pubmed
Qu,
Differential modulation of sodium channel gating and persistent sodium currents by the beta1, beta2, and beta3 subunits.
2001,
Pubmed
Qu,
Functional roles of the extracellular segments of the sodium channel alpha subunit in voltage-dependent gating and modulation by beta1 subunits.
1999,
Pubmed
,
Xenbase
Rogers,
Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
1996,
Pubmed
Schnur,
NMR analysis of interaction of LqhalphaIT scorpion toxin with a peptide corresponding to the D4/S3-S4 loop of insect para voltage-gated sodium channel.
2008,
Pubmed
,
Xenbase
Sheets,
The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4.
1999,
Pubmed
Shichor,
Domain 2 of Drosophila para voltage-gated sodium channel confers insect properties to a rat brain channel.
2002,
Pubmed
,
Xenbase
Strichartz,
Rapid voltage-dependent dissociation of scorpion alpha-toxins coupled to Na channel inactivation in amphibian myelinated nerves.
1986,
Pubmed
Tejedor,
Photoaffinity labeling of the receptor site for alpha-scorpion toxins on purified and reconstituted sodium channels by a new toxin derivative.
1990,
Pubmed
Thomsen,
Localization of the receptor site for alpha-scorpion toxins by antibody mapping: implications for sodium channel topology.
1989,
Pubmed
Tombola,
How does voltage open an ion channel?
2006,
Pubmed
Ulbricht,
Sodium channel inactivation: molecular determinants and modulation.
2005,
Pubmed
Wallner,
Modulation of the skeletal muscle sodium channel alpha-subunit by the beta 1-subunit.
1993,
Pubmed
,
Xenbase
Wang,
Mapping the receptor site for alpha-scorpion toxins on a Na+ channel voltage sensor.
2011,
Pubmed
Warmke,
Functional expression of Drosophila para sodium channels. Modulation by the membrane protein TipE and toxin pharmacology.
1997,
Pubmed
,
Xenbase
Weinberger,
Positions under positive selection--key for selectivity and potency of scorpion alpha-toxins.
2010,
Pubmed
West,
A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.
1992,
Pubmed
,
Xenbase
Yang,
The position of the fourth segment of domain 4 determines status of the inactivation gate in Na+ channels.
2003,
Pubmed
,
Xenbase
Yu,
Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2.
2003,
Pubmed
Zlotkin,
The insect voltage-gated sodium channel as target of insecticides.
1999,
Pubmed
