Tarantula toxins interacting with voltage sensors in potassium channels

Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Toxicon (Impact Factor: 2.49). 03/2007; 49(2):213-30. DOI: 10.1016/j.toxicon.2006.09.024
Source: PubMed


Voltage-activated ion channels open and close in response to changes in membrane voltage, a process that is crucial for electrical signaling in the nervous system. The venom from many poisonous creatures contains a diverse array of small protein toxins that bind to voltage-activated channels and modify the gating mechanism. Hanatoxin and a growing number of related tarantula toxins have been shown to inhibit activation of voltage-activated potassium (K(v)) channels by interacting with their voltage-sensing domains. This review summarizes our current understanding of the mechanism by which these toxins alter gating, the location of the toxin receptor within K(v) channels and the disposition of this receptor with respect to the lipid membrane. The conservation of tarantula toxin receptors among voltage-activated ion channels will also be discussed.

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    • "First, members of both these channel families possess tetrameric architectures where each monomer consists of six transmembrane segments (S1–S6) with the S5–S6 region forming the pore (Fig. 1)3561920. Second, both TRP and Kv channels display pharmacological similarities, such as modulation by isostructural cystine knot peptide toxins—Kv channels are inhibited by voltage sensor-binding toxins1921, and TRPV1 is activated by double-knot toxin (DkTx)1122 and vanillotoxins23. Indeed, individual vanillotoxins have been reported to cross-react with TRPV1 and Kv2.123. "
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    ABSTRACT: The molecular mechanisms underlying the activation of Transient Receptor Potential (TRP) ion channels are poorly understood when compared to those of the voltage-activated potassium (Kv) channels. The architectural and pharmacological similarities between the members of these two families of channels suggest that their structure-function relationships may have common features. We explored this hypothesis by replacing previously identified domains and critical structural motifs of the membrane-spanning portions of Kv2.1 with corresponding regions of two TRP channels, TRPM8 and TRPV1. Our results show that the S3b-S4 paddle motif of Kv2.1, but not other domains, can be replaced by the analogous regions of both TRP channels without abolishing voltage-activation. In contrast, replacement of portions of TRP channels with those of Kv2.1 consistently yielded non-functional channels. Taken together, these results suggest that most structural elements within TRP channels and Kv channels are not sufficiently related to allow for the creation of hybrid channels.
    Full-text · Article · Mar 2013 · Scientific Reports
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    • "Several tarantula and sea anemone toxins (e.g., hanatoxin , BDS-II) are well-known gating modifiers of Kv channels (Swartz, 2007; Wang et al., 2007). Both peptide toxins also stabilize the resting state, but their mechanism differs from the polyether toxin gambierol. "
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    ABSTRACT: Voltage-gated potassium (Kv) and sodium (Nav) channels are key determinants of cellular excitability and serve as targets of neurotoxins. Most marine ciguatoxins potentiate Nav channels and cause ciguatera seafood poisoning. Several ciguatoxins have also been shown to affect Kv channels, and we showed previously that the ladder-shaped polyether toxin gambierol is a potent Kv channel inhibitor. Most likely, gambierol acts via a lipid-exposed binding site, located outside the K(+) permeation pathway. However, the mechanism by which gambierol inhibits Kv channels remained unknown. Using gating and ionic current analysis to investigate how gambierol affected S6 gate opening and voltage-sensing domain (VSD) movements, we show that the resting (closed) channel conformation forms the high-affinity state for gambierol. The voltage dependence of activation was shifted by >120 mV in the depolarizing direction, precluding channel opening in the physiological voltage range. The (early) transitions between the resting and the open state were monitored with gating currents, and provided evidence that strong depolarizations allowed VSD movement up to the activated-not-open state. However, for transition to the fully open (ion-conducting) state, the toxin first needed to dissociate. These dissociation kinetics were markedly accelerated in the activated-not-open state, presumably because this state displayed a much lower affinity for gambierol. A tetrameric concatemer with only one high-affinity binding site still displayed high toxin sensitivity, suggesting that interaction with a single binding site prevented the concerted step required for channel opening. We propose a mechanism whereby gambierol anchors the channel's gating machinery in the resting state, requiring more work from the VSD to open the channel. This mechanism is quite different from the action of classical gating modifier peptides (e.g., hanatoxin). Therefore, polyether toxins open new opportunities in structure-function relationship studies in Kv channels and in drug design to modulate channel function.
    Full-text · Article · Mar 2013 · The Journal of General Physiology
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    • "Protein toxins from venomous organisms have been invaluable tools for probing ion channel structure and mechanisms. A diversity of venom toxins interact with voltage-activated ion channels, with the external vestibule of the pore (Miller, 1995; French and Terlau, 2004; French and Zamponi, 2005), and with the S1–S4 voltage-sensing domains serving as particularly common targets (Rogers et al., 1996; Swartz and MacKinnon, 1997b; Alabi et al., 2007; Swartz, 2007; Bosmans et al., 2008). In the case of Nav channels, toxins targeting S1–S4 voltage-sensing domains can inhibit or facilitate opening (Rogers et al., 1996; Cestèle et al., 1998, 2006; French and Zamponi, 2005; Bosmans et al., 2008; Bosmans and Swartz, 2010; Wang et al., 2011; Leipold et al., 2012; Zhang et al., 2012); however, in the case of both Kv and Cav channels, only inhibitors have thus far been described (French and Zamponi, 2005; Swartz, 2007). "
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    ABSTRACT: Voltage-activated ion channels open and close in response to changes in membrane voltage, a property that is fundamental to the roles of these channels in electrical signaling. Protein toxins from venomous organisms commonly target the S1-S4 voltage-sensing domains in these channels and modify their gating properties. Studies on the interaction of hanatoxin with the Kv2.1 channel show that this tarantula toxin interacts with the S1-S4 domain and inhibits opening by stabilizing a closed state. Here we investigated the interaction of hanatoxin with the Shaker Kv channel, a voltage-activated channel that has been extensively studied with biophysical approaches. In contrast to what is observed in the Kv2.1 channel, we find that hanatoxin shifts the conductance-voltage relation to negative voltages, making it easier to open the channel with membrane depolarization. Although these actions of the toxin are subtle in the wild-type channel, strengthening the toxin-channel interaction with mutations in the S3b helix of the S1-S4 domain enhances toxin affinity and causes large shifts in the conductance-voltage relationship. Using a range of previously characterized mutants of the Shaker Kv channel, we find that hanatoxin stabilizes an activated conformation of the voltage sensors, in addition to promoting opening through an effect on the final opening transition. Chimeras in which S3b-S4 paddle motifs are transferred between Kv2.1 and Shaker Kv channels, as well as experiments with the related tarantula toxin GxTx-1E, lead us to conclude that the actions of tarantula toxins are not simply a product of where they bind to the channel, but that fine structural details of the toxin-channel interface determine whether a toxin is an inhibitor or opener.
    Preview · Article · Feb 2013 · The Journal of General Physiology
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