Peptides and genes coding for scorpion toxins that affect ion-channels

Possani, Lourival D.; Merino, Enrique; Corona, Miguel; Bolívar, Francisco; Becerril, Baltazar

doi:10.1016/s0300-9084(00)01167-6

Cited by 277 publications

(164 citation statements)

References 33 publications

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“…Interestingly, a similar, slow time-course of drug action has been reported for Cltx blockade of single Cl − channels recorded from reactive astrocytes (Dalton et al, 2003). This is unlike the effects of scorpion peptides on other ion channels, which typically occur within milliseconds (Possani et al, 2000).…”

Section: A Putative CL − Channel Inhibitor (Cltx) Is Currently In Clisupporting

confidence: 54%

A role for ion channels in glioma cell invasion

McFerrin¹,

2005

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Many cells, including neuronal and glial progenitor cells, stem cells and microglial cells, have the capacity to move through the extracellular spaces of the developing and mature brain. This is particularly pronounced in astrocyte-derived tumors, gliomas, which diffusely infiltrate the normal brain. Although a significant body of literature exists regarding signals that are involved in the guidance of cells and their processes, little attention has been paid to cell-shape and cell-volume changes of migratory cells. However, extracellular spaces in the brain are very narrow and represent a major obstacle that requires cells to dynamically regulate their volume. Recent studies in glioma cells show that this involves the secretion of Cl − and K + with water. Pharmacological inhibition of Cl − channels impairs their ability to migrate and limits tumor progression in experimental tumor models. One Cl − -channel inhibitor, chlorotoxin, is currently in Phase II clinical trials to treat malignant glioma. This article reviews our current knowledge of cell-volume changes and the role of ion channels during the migration of glioma cells. It also discusses evidence that supports the importance of channel-mediated cell-volume changes in the migration of immature neurons and progenitor cells during development. New unpublished data is presented, which demonstrates that Cl − and K + channels involved in cell shrinkage localize to lipid-raft domains on the invadipodia of glioma cells and that their presence might be regulated by trafficking of these proteins in and out of lipid rafts.

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Section: A Putative CL − Channel Inhibitor (Cltx) Is Currently In Clisupporting

confidence: 54%

A role for ion channels in glioma cell invasion

McFerrin¹,

2005

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“…Solution NMR data revealed that -hefutoxin 1 adopts a unique three-dimensional fold of two parallel ␣-helices held together by two disulfide bridges and separated by a loop with no evidence of ␤-sheets. All known scorpion toxins possess a highly conserved threedimensional arrangement comprising double-or triplestranded antiparallel ␤-sheet and a stretch of ␣-helix maintained by a couple of disulfide bridges (4,12).…”

Section: Discussionmentioning

confidence: 99%

“…Scorpion toxins that inhibit Cl Ϫ channels are ϳ36 amino acids long with four disulfide bridges (10,11). Scorpion toxins possess a highly conserved secondary structure arrangement comprising double-or triplestranded antiparallel ␤-sheet and a stretch of ␣-helix maintained by a couple of disulfide bridges (4,12).…”

mentioning

confidence: 99%

κ-Hefutoxin1, a Novel Toxin from the ScorpionHeterometrus fulvipes with Unique Structure and Function

Srinivasan¹,

Vaithiyalingam²,

Huys³

et al. 2002

Journal of Biological Chemistry

131

112

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An important and exciting challenge in the postgenomic era is to understand the functions of newly discovered proteins based on their structures. The main thrust is to find the common structural motifs that contribute to specific functions. Using this premise, here we report the purification, solution NMR, and functional characterization of a novel class of weak potassium channel toxins from the venom of the scorpion Heterometrus fulvipes. These toxins, -hefutoxin1 and -hefutoxin2, exhibit no homology to any known toxins. NMR studies indicate that -hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any ␤؊sheets. Based on the presence of the functional diad (Tyr 5 /Lys 19 ) at a distance (6.0 ؎ 1.0 Å) comparable with other potassium channel toxins, we hypothesized its function as a potassium channel toxin. -Hefutoxin 1 not only blocks the voltage-gated K ؉ -channels, Kv1.3 and Kv1.2, but also slows the activation kinetics of Kv1.3 currents, a novel feature of -hefutoxin 1, unlike other scorpion toxins, which are considered solely pore blockers. Alanine mutants (Y5A, K19A, and Y5A/K19A) failed to block the channels, indicating the importance of the functional diad.

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“…37) and scorpine, a defensin and antimalaria agent (38). The findings described here should not be taken as unusual since of the 100,000 components estimated to exist in scorpion venoms alone, only over 300 components have been studied thus far (36,39,40). Most of the studies reported in the literature deal with peptides from 26 to 76 amino acid residues long, but very few, if any, studies have been performed with the low molecular weight components of these venoms, which elute from the Sephadex G-50 column in fraction V.…”

Section: Discussionmentioning

confidence: 65%

Tetrapandins, a New Class of Scorpion Toxins That Specifically Inhibit Store-operated Calcium Entry in Human Embryonic Kidney-293 Cells

Shalabi

Zamudio

et al. 2004

Journal of Biological Chemistry

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Venoms from 14 snakes and four scorpions were screened for inhibitory activities toward store-operated Ca 2؉ entry (SOCE) in human embryonic kidney-293 cells. An inhibitory activity was found in venom from the African scorpion Pandinus imperator. The active agent of this venom was purified by gel filtration and reverse-phase high pressure liquid chromatography methods. Sequence information on the purified fraction, by automatic Edman degradation and mass spectrometry analysis, identified the activity as being contained in two tetrapeptides, which we have named tetrapandins. We demonstrate that synthesized tetrapandins have inhibitory activity for SOCE in human embryonic kidney-293 cells while having no effect on either thapsigarginor carbachol-stimulated release of Ca 2؉ stores. These toxins should be extremely useful in future studies to determine downstream events regulated by SOCE as well as to determine whether multiple pathways exist for thapsigargin-stimulated Ca 2؉ entry.

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Peptides and genes coding for scorpion toxins that affect ion-channels

Cited by 277 publications

References 33 publications

A role for ion channels in glioma cell invasion

A role for ion channels in glioma cell invasion

κ-Hefutoxin1, a Novel Toxin from the ScorpionHeterometrus fulvipes with Unique Structure and Function

Tetrapandins, a New Class of Scorpion Toxins That Specifically Inhibit Store-operated Calcium Entry in Human Embryonic Kidney-293 Cells

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