Modulation of voltage-gated Na+ and K+ channels by pumiliotoxin 251D: A “joint venture” alkaloid from arthropods and amphibians

Vandendriessche, Thomas; Abdel–Mottaleb, Yousra; Maertens, Chantal; Cuypers, Eva; Sudau, Alexander; Nubbemeyer, U.; Mebs, Dietrich; Tytgat, Jan

doi:10.1016/j.toxicon.2007.10.011

Cited by 19 publications

(18 citation statements)

References 32 publications

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“…Nav1.4 is a known molecular target of three classes of alkaloids found in poison frogs and their diets: BTX, PTX, and HTX (Daly and Spande 1986;Vandendriessche et al 2008;Saporito et al 2009). Hence, we expected to find AA replacements at alkaloid binding sites of Nav1.4 that evolved in the ancestor of dendrobatids, with additional replacements occurring in the lineages of chemically defended species.…”

Section: Discussionmentioning

confidence: 99%

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Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs

Tarvin

Santos

O’Connell

et al. 2016

Molecular Biology and Evolution

108

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Complex phenotypes typically have a correspondingly multifaceted genetic component. However, the genotype-phenotype association between chemical defense and resistance is often simple: genetic changes in the binding site of a toxin alter how it affects its target. Some toxic organisms, such as poison frogs (Anura: Dendrobatidae), have defensive alkaloids that disrupt the function of ion channels, proteins that are crucial for nerve and muscle activity. Using protein-docking models, we predict that three major classes of poison frog alkaloids (histrionicotoxins, pumiliotoxins, and batrachotoxins) bind to similar sites in the highly conserved inner pore of the muscle voltage-gated sodium channel, Nav1.4. We predict that poison frogs are somewhat resistant to these compounds because they have six types of amino acid replacements in the Nav1.4 inner pore that are absent in all other frogs except for a distantly related alkaloid-defended frog from Madagascar, Mantella aurantiaca. Protein-docking models and comparative phylogenetics support the role of these replacements in alkaloid resistance. Taking into account the four independent origins of chemical defense in Dendrobatidae, phylogenetic patterns of the amino acid replacements suggest that 1) alkaloid resistance in Nav1.4 evolved independently at least seven times in these frogs, 2) variation in resistance-conferring replacements is likely a result of differences in alkaloid exposure across species, and 3) functional constraint shapes the evolution of the Nav1.4 inner pore. Our study is the first to demonstrate the genetic basis of autoresistance in frogs with alkaloid defenses.

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Section: Discussionmentioning

confidence: 99%

“…These compounds either prevent the passage of sodium ions by blocking the channel pore ( fig. 1A) or allow increased passage of sodium ions by preventing channel inactivation (Daly et al 1985;Vandendriessche et al 2008). Such effects can cause temporary paralysis and even death (Karalliedde 1995).…”

Section: Introductionmentioning

confidence: 99%

Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs

Tarvin

Santos

O’Connell

et al. 2016

Molecular Biology and Evolution

108

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“…hK v 1.3 channels were prepared as previously described (31). Stage-V and -VI Xenopus laevis oocytes were harvested by partial ovariectomy under anaesthesia (3-aminobenzoic acid ethyl ester methanesulfonate salt, 0.5 g/l, Sigma).…”

Section: Methodsmentioning

confidence: 99%

Purification, molecular cloning and functional characterization of HelaTx1 (Heterometrus laoticus): The first member of a new κ-KTX subfamily

Vandendriessche

Kopljar

Jenkins

et al. 2012

Biochemical Pharmacology

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Given their medical importance, most attention has been paid towards the venom composition of scorpions of the Buthidae family. Nevertheless, research has shown that the venom of scorpions of other families is also a remarkable source of unique peptidyl toxins. The κ-KTX family of voltage-gated potassium channel (VGPC) scorpion toxins is hereof an example. From the telson of the scorpion Heterometrus laoticus (Scorpionidae), a peptide, Hl15-1-1, with unique primary sequence was purified through HPLC and sequenced by Edman degradation. Based on the amino acid sequence, the peptide could be cloned and the cDNA sequence revealed. Hl15-1-1 was chemically synthesized and functionally characterized on VGPCs of the Shaker-related, Shaw-related and Shal-related subfamilies. Furthermore, the toxin was also tested on small- and intermediate conductance Ca2+-activated K+ channels. From the channels studied, Kv1.1 and Kv1.6 were found to be the most sensitive (Kv1.1 EC50 = 9.9 ± 1.6 μM). The toxin did not alter the activation of the channels. Competition experiments with TEA showed that the toxin is a pore blocker. Mutational studies showed that the residues E353 and Y379 in the pore of Kv1.1 act as major interaction points for binding of the toxin. Given the amino acid sequence, the predicted secondary structure and the biological activity on VGPCs, Hl15-1-1 should be included in the κ-KTX family. Based on a phylogenetic study we rearranged this family of VGPC toxins into five subfamilies and suggest that HI15-1-1 is the first member of the new KTX5 subfamily.

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“…One notable source is in the skin secretions of frogs that are found in the rain forests of Columbia, Panama, and Madagascar, and it is these secretions that have been historically used for the preparation of poisoned arrows. Pumiliotoxins (PTX) is a class of dendrobatid alkaloids that have significant pharmacological activity 2. PTX A and B were isolated in the late 1960s by Daly et al from the Panamanian poison frog Dendrobates pumilio (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Water‐ and Organo‐Dispersible Gold Nanoparticles Supported by Using Ammonium Salts of Hyperbranched Polystyrene: Preparation and Catalysis

Gao

Nishikata

Kojima

et al. 2013

Chemistry An Asian Journal

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Gold nanoparticles (1 nm in size) stabilized by ammonium salts of hyperbranched polystyrene are prepared. Selection of the R groups provides access to both water- and organo-dispersible gold nanoparticles. The resulting gold nanoparticles are subjected to studies on catalysis in solution, which include reduction of 4-nitrophenol with sodium borohydride, aerobic oxidation of alcohols, and homocoupling of phenylboronic acid. In the reduction of 4-nitrophenol, the catalytic activity is clearly dependent on the size of the gold nanoparticles. For the aerobic oxidation of alcohols, two types of biphasic oxidation are achieved: one is the catalyst dispersing in the aqueous phase, whereas the other is in the organic phase. The catalysts are reusable more than four times without loss of the catalytic activity. Selective synthesis of biphenyl is achieved by the homocoupling of phenylboronic acid catalyzed by organo-dispersible gold nanoparticles.

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Modulation of voltage-gated Na+ and K+ channels by pumiliotoxin 251D: A “joint venture” alkaloid from arthropods and amphibians

Cited by 19 publications

References 32 publications

Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs

Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs

Purification, molecular cloning and functional characterization of HelaTx1 (Heterometrus laoticus): The first member of a new κ-KTX subfamily

Water‐ and Organo‐Dispersible Gold Nanoparticles Supported by Using Ammonium Salts of Hyperbranched Polystyrene: Preparation and Catalysis

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