APETx1, a New Toxin from the Sea Anemone<i>Anthopleura elegantissima</i>, Blocks Voltage-Gated Human<i>Ether-a-go-go</i>–Related Gene Potassium Channels

Diochot, Sylvie; Loret, Erwann; Bruhn, Thomas; Béress, L.; Lazdunski, Michel

doi:10.1124/mol.64.1.59

Cited by 117 publications

(131 citation statements)

References 48 publications

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“…The toxin APEKTx1 was purified as described previously [16,17,19]. The fraction containing APEKTx1 was further purificated by RP-HPLC with a semi preparative Vydac C18 column (4.6X250 mm).…”

Section: Toxin Purificationmentioning

confidence: 99%

“…Based on structural differences and activity profile, these potassium channel toxins can be divided into 4 structural classes [11,[13][14][15]. Up to date 6 toxins from A. elegantissima have been isolated and characterized: APE1-1, APE1-2, APE2-2 and ApC which are type 1 sodium channel toxins; APETx1 a selective modifier of the human ether a go-go related gene K + channel (hERG) and APETx2 which specifically inhibits the Acid Sensing Ion Channel (ASIC3) [15][16][17][18]. In this work we present the purification, biochemical analysis and electrophysiological characterization of a very potent and selective K V 1.1 blocker which represents the newest member of the sea anemone type 2 potassium channel toxins.…”

Section: Introductionmentioning

confidence: 99%

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A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

Peigneur¹,

Billen²,

Derua³

et al. 2011

Biochemical Pharmacology

101

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 22A c c e p t e d M a n u s c r i p t Abstract Sea anemone venom is a known source of interesting bioactive compounds, including peptide toxins which are invaluable tools for studying structure and function of voltage-gated potassium channels. APEKTx1 is a novel peptide isolated from the sea anemone Anthopleura elegantissima, containing 63 amino acids cross-linked by 3 disulfide bridges. Sequence alignment reveals that APEKTx1 is a new member of the type 2 sea anemone peptides targeting voltage-gated potassium channels (K V 's), which also include the kalicludines from Anemonia sulcata. Similar to the kalicludines, APEKTx1 shares structural homology with both the basic pancreatic trypsin inhibitor (BPTI), a very potent Kunitz-type protease inhibitor, and dendrotoxins which are powerful blockers of voltage-gated potassium channels. In this study, APEKTx1 has been subjected to a screening on a wide range of 23 ion channels expressed in Xenopus leavis oocytes: 13 cloned voltage-gated potassium channels (K V 1.1-K V 1.6, K V 1.1 triple mutant, K V 2.1, K V 3.1, K V 4.2, K V 4.3, hERG, the insect channel Shaker IR), 2 cloned hyperpolarization-activated cyclic nucleotidesensitive cation non-selective channels (HCN1 and HCN2) and 8 cloned voltage-gated sodium channels (Na V 1.2-Na V 1.8 and the insect channel DmNa V 1). Our data shows that APEKTx1 selectively blocks K V 1.1 channels in a very potent manner with an IC 50 value of 0.9 nM. Furthermore, we compared the trypsin inhibitory activity of this toxin with BPTI. APEKTx1 inhibits trypsin with a dissociation constant of 124 nM. In conclusion, this study demonstrates that APEKTx1 has the unique feature to combine the dual functionality of a potent and selective blocker of K V 1.1 channels with that of a competitive inhibitor of trypsin.Keywords Anthopleura elegantissima · K V channel inhibitor · sea anemone toxin · protease inhibitor ·

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Section: Toxin Purificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

Peigneur¹,

Billen²,

Derua³

et al. 2011

Biochemical Pharmacology

101

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“…The HERG organic blockers are not sufficiently selective for the different isoforms. However, several hERG-specific peptides have become available: ErgTx1 (CnErg1; Gurrola et al, 1999), ErgTx2 (Lecchi et al, 2002), BeKm-1 (Korolkova et al, 2001), CsEKerg1 (Nastainczyk et al, 2002), and APETx1 (Diochot et al, 2003). The aim of the present study was to examine whether the above ERG1-specific peptides present selective effects on different ERG members.…”

mentioning

confidence: 99%

Species Diversity and Peptide Toxins Blocking Selectivity of Ether-à-go-go-Related Gene Subfamily K⁺ Channels in the Central Nervous System

Restano-Cassulini¹,

Korolkova²,

Diochot³

et al. 2006

Mol Pharmacol

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The ether-à -go-go-related gene (erg) K ϩ channels are known to be crucial for life in Caenorhabditis elegans (mating), Drosophila melanogaster (seizure), and humans (LQT syndrome). The erg genes known to date (erg1, erg2, and erg3) are highly expressed in various areas of the rat and mouse central nervous system (CNS), and ERG channel blockers alter firing accommodation. To assign physiological roles to each isoform, it is necessary to design pharmacological strategies to distinguish individual currents. To this purpose, we have investigated the blocking properties of specific peptide inhibitors of hERG1 channels on the human and rat isoforms. In particular, we have tested ErgTx1 (from the scorpion Centruroides noxious), BeKm-1 (from the scorpion Buthus eupeus), and APETx1 (from the sea anemone Anthopleura elegantissima). Because these peptides had different species-specific effects on the six different channels, we have also carried out a biophysical characterization of hERG2 and hERG3 channels that turned out to be different from the rat homologs. It emerged that APETx1 is exquisitely selective for ERG1 and does not compete with the other two toxins. BeKm-1 discriminates well among the three rat members. ErgTx1 is unable to block hERG2, but blocks rERG2 and has the lowest K D for hERG3. BeKm-1 and ErgTx1 compete for hERG3 but not for rERG2 blockade. Our findings should be helpful for structure-function studies and for novel CNS ERG-specific drug design.The ether-à -go-go family of voltage-dependent K ϩ channels consists of the eag, elk (eag-like), and erg (eag-related gene)

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“…For instance, the tarantula toxins JZTX-I and III bind to both Nav (see above) and Kv channels [134,145,146,149], ProTx-I interacts with Nav, Kv, and Cav channels, and ProTx-II interacts with Nav and Cav channels [148]. In addition, there are other unrelated toxins like sea-anemone toxins that affect Kv channels with a similar mechanism [151][152][153]. The amphipathic structure of the cysteine-knot toxins with a cluster of hydrophobic residues surrounded by polar residues [133] suggests that they are likely to partition into the membrane and possibly act on the VSD from there [64,[154][155][156][157].…”

Section: Toxinsmentioning

confidence: 99%

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Börjesson

Elinder

2008

Cell Biochem Biophys

119

133

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Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane.This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.3

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APETx1, a New Toxin from the Sea AnemoneAnthopleura elegantissima, Blocks Voltage-Gated HumanEther-a-go-go–Related Gene Potassium Channels

Cited by 117 publications

References 48 publications

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

Species Diversity and Peptide Toxins Blocking Selectivity of Ether-à-go-go-Related Gene Subfamily K⁺ Channels in the Central Nervous System

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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APETx1, a New Toxin from the Sea AnemoneAnthopleura elegantissima, Blocks Voltage-Gated HumanEther-a-go-go–Related Gene Potassium Channels

Cited by 117 publications

References 48 publications

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

Species Diversity and Peptide Toxins Blocking Selectivity of Ether-à-go-go-Related Gene Subfamily K+ Channels in the Central Nervous System

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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Species Diversity and Peptide Toxins Blocking Selectivity of Ether-à-go-go-Related Gene Subfamily K⁺ Channels in the Central Nervous System