Voltage-Gated Sodium Channel Toxins: Poisons, Probes, and Future Promise

Blumenthal, Kenneth M.; Seibert, Anna L.

doi:10.1385/cbb:38:2:215

Cited by 63 publications

(51 citation statements)

References 124 publications

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“…These results indicated that nonidentical amino acids of the DIV S3-S4 loop participate in scorpion α-toxin and sea anemone toxin binding to overlapping sites and that neighboring amino acid residues in the DIV S3 segment contribute to the difference in scorpion α-toxin binding affinity between cardiac and neuronal Na v channels. Also, further experiments using AP-B on Na v 1.2 or Na v 1.5 mutants have suggested the involvement of this loop region and more specific Glu 1613 and Glu 1616 for Na v 1.2 and Asp1612 for Na v 1.5 (see Figure 3) (Benzinger et al, 1998;Blumenthal and Seibert, 2003;Honma and Shiomi, 2006). Other research groups, focusing on finding residues important for scorpion α-toxin binding, have also highlighted residues in this loop region in DIV (Leipold et al, 2004).…”

Section: Na V Channels and Site 3 Toxinsmentioning

confidence: 94%

“…Furthermore, researchers in the lab of Dr. Blumenthal have shown that Leu 18 is an absolute requirement for the binding of AP-B to its target (Blumenthal and Seibert, 2003;Honma and Shiomi, 2006). Neighboring residues are either less sensitive, or their sensitivity is dependent on the nature of the mutation, especially the introduction of negative charges at these positions that is poorly tolerated.…”

Section: Structure-function Relationship Of Sea Anemone Toxinsmentioning

confidence: 99%

“…Only two residues located outside the flexible loop region (Trp 33 and Lys 37 ) seem to be indispensable for pharmacological activity. It has been shown that Lys 37 can interact directly with Asp 1612 of rat Na v 1.5 (Benzinger et al, 1998;Blumenthal and Seibert, 2003).…”

Section: Structure-function Relationship Of Sea Anemone Toxinsmentioning

confidence: 99%

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Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels

Bosmans

Tytgat

2007

Toxicon

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Sea anemones produce a myriad of toxic peptides and proteins of which a large group acts on voltagegated Na + channels. However, in comparison to other organisms, their venoms and toxins are poorly studied. Most of the known voltage-gated Na + channel toxins isolated from sea anemone venoms act on neurotoxin receptor site 3 and inhibit the inactivation of these channels. Furthermore, it seems that most of these toxins have a distinct preference for crustaceans. Given the close evolutionary relationship between crustaceans and insects, it is not surprising that sea anemone toxins also profoundly affect insect voltage-gated Na + channels, which constitutes the scope of this review. For this reason, these peptides can be considered as insecticidal lead compounds in the development of insecticides.

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Section: Na V Channels and Site 3 Toxinsmentioning

confidence: 94%

Section: Structure-function Relationship Of Sea Anemone Toxinsmentioning

confidence: 99%

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Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels

Bosmans

Tytgat

2007

Toxicon

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“…A multitude of animal toxins target sodium channel voltage-sensors (Cestele and Catterall, 2000;Catterall, 2002;Blumenthal and Seibert, 2003). Many of these agents alter sodium current activity and channel gating with distinct voltage-dependent properties, suggesting that they differentially impact the voltage-sensors of VGSCs.…”

Section: Introductionmentioning

confidence: 99%

Gating-Pore Currents Demonstrate Selective and Specific Modulation of Individual Sodium Channel Voltage-Sensors by Biological Toxins

2014

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Voltage-gated sodium channels are critical determinants of nerve and muscle excitability. Although numerous toxins and small molecules target sodium channels, identifying the mechanisms of action is challenging. Here we used gating-pore currents selectively generated in each of the voltage-sensors from the four a-subunit domains (DI-DIV) to monitor the activity of individual voltage-sensors and to investigate the molecular determinants of sodium channel pharmacology. The tarantula toxin huwentoxin-IV (HWTX-IV), which inhibits sodium channel current, exclusively enhanced inward gating-pore currents through the DII voltagesensor. By contrast, the tarantula toxin ProTx-II, which also inhibits sodium channel currents, altered the gating-pore currents in multiple voltage-sensors in a complex manner. Thus, whereas HWTX-IV inhibits central-pore currents by selectively trapping the DII voltage-sensor in the resting configuration, ProTx-II seems to inhibit central-pore currents by differentially altering the configuration of multiple voltage-sensors. The sea anemone toxin anthopleurin B, which impairs open-channel inactivation, exclusively enhanced inward gating-pore currents through the DIV voltage-sensor. This indicates that trapping the DIV voltagesensor in the resting configuration selectively impairs openchannel inactivation. Furthermore, these data indicate that although activation of all four voltage-sensors is not required for central-pore current generation, activation of the DII voltagesensor is crucial. Overall, our data demonstrate that gating-pore currents can determine the mechanism of action for sodium channel gating modifiers with high precision. We propose this approach could be adapted to identify the molecular mechanisms of action for gating modifiers of various voltage-gated ion channels.

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“…Because of their high binding affinity and subtype-specific selectivity, animal toxins are powerful tools for investigation of the structure-function relationship of VGSCs (9). The voltage sensors of DII and DIV are the two most common toxin-binding sites in VGSCs (see Fig.…”

mentioning

confidence: 99%

Common Molecular Determinants of Tarantula Huwentoxin-IV Inhibition of Na+ Channel Voltage Sensors in Domains II and IV

Xiao

Jackson

Liang

et al. 2011

Journal of Biological Chemistry

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The voltage sensors of domains II and IV of sodium channels are important determinants of activation and inactivation, respectively. Animal toxins that alter electrophysiological excitability of muscles and neurons often modify sodium channel activation by selectively interacting with domain II and inactivation by selectively interacting with domain IV. This suggests that there may be substantial differences between the toxinbinding sites in these two important domains. Here we explore the ability of the tarantula huwentoxin-IV (HWTX-IV) to inhibit the activity of the domain II and IV voltage sensors. HWTX-IV is specific for domain II, and we identify five residues in the S1-S2 (Glu-753) and S3-S4 (Glu-811, Leu-814, Asp-816, and Glu-818) regions of domain II that are crucial for inhibition of activation by HWTX-IV. These data indicate that a single residue in the S3-S4 linker (Glu-818 in hNav1.7) is crucial for allowing HWTX-IV to interact with the other key residues and trap the voltage sensor in the closed configuration. Mutagenesis analysis indicates that the five corresponding residues in domain IV are all critical for endowing HWTX-IV with the ability to inhibit fast inactivation. Our data suggest that the toxin-binding motif in domain II is conserved in domain IV. Increasing our understanding of the molecular determinants of toxin interactions with voltage-gated sodium channels may permit development of enhanced isoform-specific voltage-gating modifiers.Voltage-gated sodium channels (VGSCs) 3 play critical roles in the generation and propagation of action potentials. Nine VGSC ␣ subunit subtypes (Nav1.1-1.9) have been cloned and characterized from mammals (1). These subtypes are expressed in different excitable tissues and are involved in distinct physiological functions such as neurotransmitter release, muscle contraction, secretion, and pain sensation (2-4). The nine ␣ subunits share a common four-domain (DI-DIV) structure, in which each domain has six transmembrane segments (S1-S6) (1). Based on distinct functional behaviors during channel activity, the six transmembrane segments are generally separated into two structural components (5). The central pore module is the basis for the ion conduction pathway and is formed by the S5-S6 region of the channel. The voltage sensor modules are formed by the S1-S4 regions and are essentially independent structures that directly respond to changes in the transmembrane potential with conformational alterations that are coupled to opening and closing of the pore module. VGSCs undergo voltage-dependent activation subsequently followed by fast inactivation through successive activities of the voltage sensors in the four domains. The S4 segments in the voltage sensors of DI, DII, and DIII are determinants of channel activation, whereas that of DIV is predominantly involved in channel inactivation (5-8). The four membrane-spanning segments (S1-S4) of the voltage sensors of mammal VGSCs exhibit high sequence similarity in the four domains, but the amino acids and sequenc...

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Voltage-Gated Sodium Channel Toxins: Poisons, Probes, and Future Promise

Cited by 63 publications

References 124 publications

Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels

Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels

Gating-Pore Currents Demonstrate Selective and Specific Modulation of Individual Sodium Channel Voltage-Sensors by Biological Toxins

Common Molecular Determinants of Tarantula Huwentoxin-IV Inhibition of Na+ Channel Voltage Sensors in Domains II and IV

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