Voltage Sensor–Trapping

Cestèle, Sandrine; Qu, Yusheng; Rogers, John C.; Rochat, Hervé; Scheuer, Todd; Catterall, William A.

doi:10.1016/s0896-6273(00)80606-6

Cited by 302 publications

(224 citation statements)

References 55 publications

(21 reference statements)

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“…6, the surface of Magi 5 is highly positively charged as a result of its five Lys residues, whereas there is only one negatively charged residue, Glu 14 . By contrast, the opposite face of Magi 5 is not only lacking in charged side chains but is largely nonpolar (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In Magi 5 it appears that the surface around Lys 13 , Glu 14 , and Trp 18 is important for VGSC binding (residues 15, 16, and 17 are two Cys and a Gly, respectively, which were not substituted). Asn 19 , which is also essential for activity, points away from this surface; a nearby side chain, Thr 5 , is not critical for activity but replacement with Ala reduces activity.…”

Section: Discussionmentioning

confidence: 99%

“…Leu 23 is slightly further away, and its replacement with Ala reduces activity only slightly. It appears that Magi 5 makes extensive contacts with the sodium channel, with at least one hydrophobic surface centered on Phe 6 , Ile 25 , Met 27 , and Pro 28 playing a key role, and another, more polar, surface encompassing Lys 10 , Glu 14 , and Trp 18 , also being important (Fig. 6B).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies on the binding of scorpion ␤-toxins to VGSCs have highlighted the importance of VGSC DII as a whole and more specifically Pro 782 in DII S1-S2, Gly 845 in DII S3-S4, Arg 850 and Arg 853 in DII for binding of ␤-toxins to channels (6,14,48,49). Mutagenesis studies on scorpion ␤-toxins themselves have also revealed a number of residues critical for the pharmacological activity toward either insects or mammals (16 -20).…”

Section: Discussionmentioning

confidence: 99%

“…This site is also recognized by the sea anemone toxin ATXII and spider ␦-atracotoxins (9 -12), which differ structurally but exert a similar inhibitory effect on VGSC inactivation. Scorpion ␤-toxins bind to receptor site 4, which was shown to involve domain II in mammalian VGSCs (13)(14)(15).…”

mentioning

confidence: 99%

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Solution Structure and Alanine Scan of a Spider Toxin That Affects the Activation of Mammalian Voltage-gated Sodium Channels

Corzo

Sabo

Bosmans

et al. 2007

Journal of Biological Chemistry

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Magi 5, from the hexathelid spider Macrothele gigas, is a 29-residue polypeptide containing three disulfide bridges. It binds specifically to receptor site 4 on mammalian voltage-gated sodium channels and competes with scorpion ␤-toxins, such as Css IV from Centruroides suffusus suffusus. As a consequence, Magi 5 shifts the activation voltage of the mammalian rNav1.2a channel to more hyperpolarized voltages, whereas the insect channel, DmNav1, is not affected. To gain insight into toxinchannel interactions, Magi 5 and 23 analogues were synthesized. The three-dimensional structure of Magi 5 in aqueous solution was determined, and its voltage-gated sodium channel-binding surfaces were mapped onto this structure using data from electrophysiological measurements on a series of Ala-substituted analogues. The structure clearly resembles the inhibitor cystine knot structural motif, although the triple-stranded ␤-sheet typically found in that motif is partially distorted in Magi 5. The interactive surface of Magi 5 toward voltage-gated sodium channels resembles in some respects the Janus-faced atracotoxins, with functionally important charged residues on one face of the toxin and hydrophobic residues on the other. Magi 5 also resembles the scorpion ␤-toxin Css IV, which has distinct nonpolar and charged surfaces that are critical for channel binding and has a key Glu involved in voltage sensor trapping. These two distinct classes of toxin, with different amino acid sequences and different structures, may utilize similar groups of residues on their surface to achieve the common end of modifying voltage-gated sodium channel function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Solution Structure and Alanine Scan of a Spider Toxin That Affects the Activation of Mammalian Voltage-gated Sodium Channels

Corzo

Sabo

Bosmans

et al. 2007

Journal of Biological Chemistry

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BmK AS: New scorpion neurotoxin binds to distinct receptor sites of mammal and insect voltage‐gated sodium channels

Liu

2000

J of Neuroscience Research

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This study was undertaken to assess the binding properties of BmK AS on both mammal and insect excitable cell membranes. It was found that BmK AS bound specifically to a single class of non‐interacting binding sites on both rat brain and cockroach nerve cord synaptosomes with high affinity (Kd = 1.49 ± 0.14 and 0.79 ± 0.29 nM) and low capacity (Bmax = 1.39 ± 0.09 and 6.60 ± 1.25 pmol/mg protein), respectively. Binding kinetics showed that BmK AS could bind and reach equilibrium quickly, and dissociate partially from its binding sites on both kinds of synaptosomes. The binding of BmK AS was independent of membrane potential. Veratridine could not modify the binding of BmK AS. The competitive binding assay showed that specific binding of 125I‐BmK AS could be significantly inhibited by native BmK AS, BmK AS‐1, BmK IT2 and BmK IT on both synaptosomes. Unexpectedly, only about 20–30% binding of BmK AS on mammal synaptosomes was inhibited by BmK I at 10−5–10−9 M, but not on insect synaptosomes. It thus suggests that BmK AS type neurotoxins might bind to a distinct receptor site of sodium channels on mammal and insect excitable cell membranes with a manner similar to β‐scorpion toxins. J. Neurosci. Res. 61:541–548, 2000. © 2000 Wiley‐Liss, Inc.

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Voltage‐Gated Ion Channels

Fay

Haddick

Jan

2007

Handbook of Contemporary Neuropharmacology

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This review will give an overview of the current state of knowledge about the structures of ion channels; the mechanisms of selectivity and gating; the cell biology of ion channels, including coassembly of channel subunits with other proteins and trafficking of ion channels; the physiological functions of ion channels and their roles in disease; and pharmacological tools available for the manipulation of ion channels in vitro and in vivo. While a vast array of ion channels exist with different selectivities and mechanisms of activation, some of these channel classes are reviewed in other chapters of this edition, and this chapter will focus on voltage‐gated K + , Na + , and Ca 2+ channels.

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Voltage Sensor–Trapping

Cited by 302 publications

References 55 publications

Solution Structure and Alanine Scan of a Spider Toxin That Affects the Activation of Mammalian Voltage-gated Sodium Channels

Solution Structure and Alanine Scan of a Spider Toxin That Affects the Activation of Mammalian Voltage-gated Sodium Channels

BmK AS: New scorpion neurotoxin binds to distinct receptor sites of mammal and insect voltage‐gated sodium channels

Voltage‐Gated Ion Channels

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