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: 2.58). 03/2007; 49(2):213-30. DOI: 10.1016/j.toxicon.2006.09.024
Source: PubMed

ABSTRACT 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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    • "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.
    The Journal of General Physiology 03/2013; 141(3):359-69. DOI:10.1085/jgp.201210890 · 4.57 Impact Factor
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    • "Moreover, the venom spiders belonging to the Theraphosidae family represent a plentiful source of peptides that modify the gating of K v channels [81]. Hanatoxin and seemingly others tarantula toxins shift channel opening to more depolarized voltages [81] [82] by stabilizing the resting conformation of the voltage sensor [83]. It has been suggested that these peptides interact with the voltage-sensor paddle within the lipid membrane [84] [85] [86]. "
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    ABSTRACT: Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K(+)-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K(+)-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K(+)-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms.
    Journal of Toxicology 06/2012; 2012:756358. DOI:10.1155/2012/756358
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    • "We found that PUFA molecules affecting Kv channel voltage dependence act close to the lipid-facing outer halves of S3 and S4, representing a novel pharmacological site of action distinct from those reported previously for toxins (Swartz, 2007; Kopljar et al., 2009) and potential antiepileptics (Xiong et al., 2007; Blom et al., 2009; Lange et al., 2009). We also report that PUFAs act on the final voltage sensor transition and that the effect critically depends on specific amino acid residues at the outer end of S4, suggesting a channel specificity in the PUFA effect on ion channels. "
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    ABSTRACT: Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study, we have localized the site of action for PUFAs on the voltage-gated Shaker K channel by introducing positive charges on the channel surface, which potentiated the PUFA effect. Furthermore, we found that PUFA mainly affects the final voltage sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.
    The Journal of General Physiology 06/2011; 137(6):563-77. DOI:10.1085/jgp.201110599 · 4.57 Impact Factor
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