Site-3 sea anemone toxins: Molecular probes of gating mechanisms in voltage-dependent sodium channels

Smith, Jaime J.; Blumenthal, Kenneth M.

doi:10.1016/j.toxicon.2006.09.020

Cited by 48 publications

(39 citation statements)

References 84 publications

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“…In several cases, careful channel mutagenesis studies have been performed. These studies have shown that the toxin binding sites are often complex and are dependent on either a combination of charged and hydrophobic amino acids or charge interactions alone (Swartz and MacKinnon, 1997b;Alabi et al, 2007;Catterall et al, 2007;Smith and Blumenthal, 2007;Swartz, 2007;Zhang et al, 2007;Bosmans et al, 2008;Norton and McDonough, 2008). HpTx2 is thus far unique among the ICK toxins in relying solely on hydrophobic contacts for channel interaction.…”

Section: Discussionmentioning

confidence: 99%

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

DeSimone

Lu²,

Bondarenko³

et al. 2009

Mol Pharmacol

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Section: Discussionmentioning

confidence: 99%

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

DeSimone

Lu²,

Bondarenko³

et al. 2009

Mol Pharmacol

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“…Many neurotoxins have been identified from a variety of sea anemone species using biochemical and molecular biological methods [1]. Anthopleurin A (Ap-A) and anthopleurin B (Ap-B) were obtained from Anthopleura xanthogrammica, while anthopleurin C (Ap-C) was isolated from Anthopleura elegentissima [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

“…Sea anemone toxins, a group of polypeptides consisting of 46-49 amino acid residues with three intramolecular disulfide bridges, exhibit cardiac and neuronal toxicity [3,7]. These toxins cause prolongation of action potential duration of excitable cells by delaying the inactivation process of Na ± currents [1][2][3][4][5][6][7][8][9]. Previous studies have demonstrated that the sea anemone toxins, which have been used as pharmacological tools to investigate the structure and function of Na ± channels, inhibit the inactivation of voltage-sensitive sodium channels via interacting with site-3 of the sodium channel, and therefore they are called site-3 toxins [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Effects of recombinant neurotoxins on single Na⁺ channels in isolated rat hippocampal neurons

Xiang

Wang

Cui

et al. 2009

J Biochem & Molecular Tox

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Four recombinant neurotoxins Hk2a, Hk7a, Hk8a, Hk16a, originally from a sea anemone species Anthopleura sp., were obtained by fusion expression of their genes in Escherichia coli. These neurotoxins were composed of 47 amino acid residues, among which the differences were found at positions 14, 22, 25, and 37, respectively. The effects of the four neurotoxins on single-channel current of sodium in rat hippocampal neurons were studied by cell-attached patch clamp. Each neurotoxin 2 microM could modulate the sodium channel by prolonging the opening dwell time and increasing the open probability, but did not change the amplitude of sodium channel currents. Based on the studies of the structure-function relationship, we found that Hk7a displayed the biggest increase of the open probability because His14 (from Arg14) makes its structure seem more compact in comparison with the other three toxins and Ap-A. Phe25 (Hk8a, Hk16a), which varied from Ala25 (Hk2a, Hk7a), showed that phenyl group might interfere with other key amino acid residue to decrease the activity of toxins. Arg37 (from His37) in Hk8a contributed to decrease of open probability. In our work, it was shown that these important amino acid sites might provide a reliable proof for the future pharmaceutical design.

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“…They are produced by sea anemones and have a fundamental role in the venom to help these sessile animals to immobilize their prey rapidly and to defend against predators. Neurotoxins prolong the action potential of the excitable and non-excitable membranes in sensory neurons and cardiac and skeletal muscle cells [64,115] via modifying the sodium channel gating [64,116,117] or blocking the potassium channel gating during the repolarisation stage [115]. This causes the cell to become hyperactive and to release massive amounts of neurotransmitter at synapses and neuromuscular junctions that can cause initial spastic stage followed by descending flaccid paralysis.…”

Section: Neurotoxinsmentioning

confidence: 99%

“…Among cnidarians, neurotoxins have only been retrieved from the venoms of sea anemones (class: Actiniaria). NaTxs are one of the best characterised cnidarian toxins [118,162,165] and are classified into three types (type I-III) based on the cysteine arrangement, overall structure, amino acid composition, and immunological cross reactivity [64,118,122]. The distinction between type I and type II NaTxs has been artificial, considering the similarity they share in structure and function.…”

Section: Neurotoxinsmentioning

confidence: 99%

Evolution and diversification of the cnidarian venom system

Jouiaei¹

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The phylum Cnidaria (corals, sea pens, sea anemones, jellyfish and hydroids) is the oldest venomous animal lineage (~750 million years old), making it an ideal phylum to understand the origin and diversification of venom. Cnidarians are characterised by specialised cellular structures called cnidae, which they utilise to inject mixtures of bioactive compounds or venom for predation and defence. In recent years cnidarian venoms have begun to be investigated as a potential source of novel bioactive therapeutics. However, in comparison with several venomous lineages that are relatively younger, such as snakes, cone snails and spiders, the diversification and molecular evolutionary regimes of toxins encoded by these fascinating and ancient animals remain poorly understood.The first experimental part of this thesis (Chapter 2) is comprised of the phylogenetic and molecular evolutionary histories of pharmacologically characterised cnidarian toxin families. These include peptide neurotoxins (voltage-gated Na + and K + channel-targeting toxins: NaTxs and KTxs, respectively), pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins) and small cysteine-rich peptides (SCRiPs). Our analyses show that most cnidarian toxins remain conserved under the strong influence of negative selection. A deeper analysis of the molecular evolutionary histories of neurotoxins demonstrates that type III KTxs have evolved from NaTxs under the regime of positive selection and likely represent a unique evolutionary innovation of the Actinioidea lineage. We also identify a few functionally important sites in other classes of neurotoxins and pore-forming toxins that experienced episodic adaptation. In addition, we describe the first family of neurotoxic peptides (SCRiPs) in reef-building corals, Acropora millepora, that are likely involved in the envenoming function.The third chapter describes the development of a novel venom extraction technique which is rapid, repeatable and cost effective. This technique involves using ethanol to both induce cnidae discharge and to recover venom contents in one step. Our model species is the notorious Australian box jellyfish (Chironex fleckeri) which has a notable impact on public health. By using the complementary approaches of transcriptomics, proteomics, mass spectrometry, histology, and scanning electron microscopy, this study compares the proteome profile of the new ethanol recovery based method to a previously reported protocol, based upon density purified intact cnidae and pressure induced disruption. This work not only results in the expansion of identified Australian box jellyfish venom components but also illustrates that ethanol extraction method could greatly augment future cnidarian venom proteomics research efforts.The forth chapter is constituted by previously described venom extraction technique, ethanolinduced discharge of cnidae, to rapidly and efficiently characterise venom components of the Jelly Blubber or Blue Blubber Jellyfish, Catostylus mosaicus. By us...

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Site-3 sea anemone toxins: Molecular probes of gating mechanisms in voltage-dependent sodium channels

Cited by 48 publications

References 84 publications

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

Effects of recombinant neurotoxins on single Na⁺ channels in isolated rat hippocampal neurons

Evolution and diversification of the cnidarian venom system

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Site-3 sea anemone toxins: Molecular probes of gating mechanisms in voltage-dependent sodium channels

Cited by 48 publications

References 84 publications

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

Effects of recombinant neurotoxins on single Na+ channels in isolated rat hippocampal neurons

Evolution and diversification of the cnidarian venom system

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Product

Resources

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Effects of recombinant neurotoxins on single Na⁺ channels in isolated rat hippocampal neurons