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PubMed2001

Use of fusion protein constructs to generate potent immunotherapy and protection against scorpion toxins.

We report the use of recombinant scorpion toxins in the form of fusion proteins as antigens for immunisation in rabbits and mice: the aim was to produce in these animal models protective antisera against the most lethal alpha-type toxins in the venom from the North African scorpion Androctonus australis. The cDNAs encoding AaH I, AaH II and AaH III (the three major alpha-type toxins acting on voltage-sensitive sodium channels) were fused to the sequence encoding the maltose binding protein (MBP). The constructs (MBP-AaH I, MBP-AaH II, MBP-AaH I+II and MBP-AaH III) were expressed in Escherichia coli, and resulting fusion proteins were translocated to the periplasmic space. The recombinant fusion proteins were characterised and used as antigens to generate antibodies in rabbits. These antibodies raised specifically recognised their corresponding radiolabelled-toxin with affinities in the 0.1nM range. In vitro neutralisation assays indicated that 1ml of serum raised against a mixture of fusion proteins was able to neutralise 15 LD(50) of the toxic fraction (AaH-G50) purified from the crude venom by molecular filtration through Sephadex G50. In vivo, the fusion proteins induced a long-term protection in mice against the lethal effects of AaH-G50 or of the native toxins. Ten weeks after the beginning of the immunisation programme, mice were challenged with various toxins or AaH-G50 doses. Mice were fully protected against three LD(50) of AaH-G50. Our work shows that fusion protein constructs can be used as a vaccine providing efficient immune protection against A. australis venom.

Animals↗
PubMed1997

In vivo protection against Androctonus australis hector scorpion toxin and venom by immunization with a synthetic analog of toxin II.

A synthetic peptide mimicking the North African scorpion Androctonus australis hector toxin II was designed and produced by chemical solid-phase synthesis. It contains the entire sequence of toxin II (64 amino acid residues), with each half-cystine being replaced by the isosteric residue a-aminobutyric acid, and was thus devoid of disulfide bridges. This construct was totally nontoxic in mice even if large amounts, equivalent to 1000 times the LD50 of the original toxin, were injected by the intracerebroventricular route. The synthetic peptide, either as a monomer or polymerized by means of glutaraldehyde, induced the production of antitoxin neutralizing antibodies in immunized mice and rabbits. After three injections with either the monomeric or polymerized synthetic peptide, the immunized mice were protected against several lethal doses of the corresponding native toxin or scorpion venom. Six months after immunization, the mice were completely protected against challenge with eight LD50 of the original toxin. The protection was better when the polymerized synthetic peptide was used. One month after the start of the immunization program, it showed a good correlation between antibody titer and protection. However, antibody titer decreased with time but protection remained high. This suggests that additional factors other than circulating antibodies play a role in protective activity.

Animals↗
PubMedDate not supplied

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

Most scorpion toxins are ligand peptides that recognize and bind to integral membrane proteins known as ion-channels. To date there are at least 202 distinct sequences described, obtained from 30 different species of scorpions, 27 from the family Buthidae and three from the family Scorpionidae. Toxins that recognize potassium and chloride channels are usually from 29 to 41 amino acids long, stabilized by three or four disulfide bridges, whereas those that recognize sodium channels are longer, 60 to 76 amino acid residues, compacted by four disulfide bridges. Toxins specific for calcium channels are scarcely known and have variable amino acid lengths. The entire repertoire of toxins, independently of their specificity, was analyzed together by computational programs and a phylogenetic tree was built showing two separate branches. The K(+) and Cl(-) channel specific toxins are clustered into 14 subfamilies, whereas those of Na(+) and Ca(2+) specific toxins comprise at least 12 subfamilies. There are clear similarities among them, both in terms of primary sequence and the main three-dimensional folding pattern. A dense core formed by a short alpha helix segment and several antiparallel beta-sheet stretches, maintained by disulfide pairing, seems to be a common structural feature present in all toxins. The physiological function of these peptides is manifested by a blockage of ion passage through the channels or by a modification of the gating mechanism that controls opening and closing of the ion pore.

Amino Acid Sequence↗
PubMed1976

[Spectroscopic study of the structural changes of scorpion hemocyanin, induced by pH variations and addition of various salts].

Structural modifications of the scorpion haemocyanin induced by pH variations and salt addition are studied by U.V. absorption, fluorescence, circular dichroism and light scattering. Haemocyanin fluorescence is due to both aromatic amino-acids tyrosine and tryptophan. Deoxygenation or denaturation lead to a fourfold enhancement of its intensity. At acidic pH the active site is modified and the protein is dissociated, but at alkaline pH the haemocyanin aggregates. The addition of different salts (sodium citrate, potassium bromide and iodide...) involves protein dissociation, the amplitude of which depends on the anion. But pH variations and salt addition don't change the haemocyanin secondary structure as shown by circular dichroism. The C.D. spectrum of scorpion haemocyanin exhibits the characteristic bands of Arthropod haemocyanine.

Animals↗
PubMed1998

Synthetic peptides as tools to investigate the structure and pharmacology of potassium channel-acting short-chain scorpion toxins.

In the last decade, numerous polypeptide toxins acting on ion channels have been isolated and characterized from diverse scorpion venoms. These toxins are useful pharmacological probes to study ion-specific channel proteins because they interact selectively with these channels and modulate their activities. Since low amounts of natural toxins can be isolated from scorpion venoms, the chemical synthesis approach is extremely useful to produce larger quantities of toxins and toxin analogs. This report is a succinct overview of the possibilities offered by the chemical synthesis to investigate pharmacological and structural properties of these compounds.

Amino Acid Sequence↗
PubMed2002

Release of gamma-[(3)H]aminobutyric acid in rat brain cortical slices by alpha-scorpion toxin.

In this paper, the effect of the alpha-scorpion toxin tityustoxin (TsTX) in the release of gamma-[(3)H]aminobutyric acid ([(3)H]GABA) from rat brain cortical slices is described. The TsTX-stimulatory effect on the release of [(3)H]GABA was dependent on incubation time and TsTX concentration, having an EC(50) of 0.33 microM. Tetrodotoxin (TTX) completely inhibited the TsTX action on [(3)H]GABA release. The scorpion toxin effect was calcium-dependent and involves P/Q calcium channels. beta-Alanine also induces the release of [(3)H]GABA that was not inhibited by TTX but was additive in the presence of TsTX. The data suggest a neuronal origin for the release of [(3)H]GABA by TsTX.

Animals↗
PubMed2001

The scorpion alpha-like toxin Lqh III specifically alters sodium channel inactivation in frog myelinated axons.

The effects of 1-100 nM Lqh III, an alpha-like toxin isolated from the scorpion Leiurus quinquestriatus hebraeus, were assessed on the nodal membrane potential and ionic currents of single frog myelinated axons. In current-clamped axons, Lqh III increased the duration of action potentials without markedly affecting the peak amplitude and the resting membrane potential. The toxin was less effective when the resting membrane potential of axons was increasingly more positive. The Lqh III-induced increase in action potential duration was not due to the blockade of K(+) channels, since the toxin had no significant effect upon the K(+) current. In contrast, Lqh III inhibited the inactivation of a fraction of the Na(+) current, leading to a maintained late inward Na(+) current which represented about 45% of the peak Na(+) current, as observed during long-lasting depolarisations and in steady-state Na(+) current inactivation-voltage relationships when the pre-pulse potential was more positive than about -30mV. The activation kinetics of the late Na(+) current were well described by a single exponential whose time constant was 8.53+/-0.78 ms (n=3). Finally, Lqh III slowed the time-course of the remaining peak Na(+) current inactivation by altering initial amplitudes (to time zero of depolarisation) and time constants of its fast and slow phases. No significant additional effect was detected during the action of the toxin. In conclusion, we propose that, in frog myelinated axons, the effects of Lqh III are those typically attributed to classical scorpion alpha-toxins.

Action Potentials↗
PubMed2001

Spider neurotoxins block the beta scorpion toxin-induced calcium uptake in rat brain cortical synaptosomes.

In this paper we describe the effects of the beta scorpion toxin Tityus gamma (TiTX gamma) and spider neurotoxins Tx3-3 and Tx3-4 in the (45)Ca(2+) uptake in synaptosomes. The TiTX gamma-stimulatory effect on (45)Ca(2+) uptake in synaptosomes was inhibited omega-Conotoxin MVIIC (omega-CgTX MVIIC) (0.1 microM) and omega-Agatoxin IVA (0.1 microM) by 70% and 41%, respectively. omega-CgTX MVIIC (1.0 microM) almost completely blocked the TiTX gamma-induced (45)Ca(2+) uptake in synaptosomes. Verapamil (1.0 microM) and omega-Conotoxin GVIA (0.1 microM) had no effect in the scorpion toxin-induced (45)Ca(2+) influx. The spider neurotoxins Tx3-3 and Tx3-4 inhibited the TiTX gamma-induced calcium uptake with an IC(50) of 10.0 and 30.0 nM, respectively. It is suggested that spider neurotoxins Tx3-3 and Tx3-4 blocking effect in the TiTX gamma-induced calcium uptake involves P/Q-type calcium channels.

Animals↗
PubMed1999

Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-K(alpha) and pandinustoxin-K(alpha).

The scorpion venom peptide toxins tityustoxin-K(alpha) (TsTx-K(alpha)) and pandinustoxin-K(alpha) (PiTx-K(alpha)) are novel, highly potent and selective blockers of voltage-activated K+ channels. PiTx-K(alpha) preferentially blocks rapidly inactivating (A-type) K+ channels whereas TsTx-K(alpha) is selective for slowly inactivating (delayed rectifier-type) channels. K+ channel blockers are known to induce seizures, but the specific K channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K+ channel type-specific scorpion toxins and the selective K+ channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K+ channels, and paxilline, a selective blocker of large conductance (maxi K) Ca(2+)-activated K+ channels. Intracerebroventricular injection of recombinant TsTx-K(alpha) and PiTx-K(alpha) in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity (status epilepticus), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50% of animals (CD50) for TsTx-K(alpha) and PiTx-K(alpha) were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD50, 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 microg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin-induced seizures, but the NMDA receptor antagonists (R)-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K+ channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca(2+)-activated K+ channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.

4-Aminopyridine↗
PubMed2004

Identification of allergens in the venom of the common striped scorpion.

BACKGROUND: The common striped scorpion, Centruroides vittatus, is endemic to the southwestern United States and causes thousands of human stings annually. Immediate hypersensitivity reactions to C. vittatus venom have been reported. OBJECTIVES: To identify specific IgE in 11 patients with immediate hypersensitivity to C. vittatus and to characterize the allergens present in the venom. METHODS: Skin testing to dialyzed, filtered venom was performed in 5 patients. Immunoglobulin E immunoblots to whole milked venom was accomplished with serum samples from 8 patients. Enzymatic properties of whole venom were also determined. RESULTS: C. vittatus venom was found to contain 150 microg/microL of protein. Four of 5 patients tested had positive skin test reactions to the purified venom extract, with no late reactions. In all 8 patients, sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated multiple proteins, 9 of which were identified as allergens on IgE immunoblots, ranging in size from 30 to 170 kD. Enzymatic activity was found to include phospholipase A, alkaline phosphatase, esterase, esterase lipase, and acid phosphatase. CONCLUSIONS: C. vittatus envenomation may result in immediate hypersensitivity reactions in susceptible individuals. Venom specific IgE can be identified by using skin tests and IgE immunoblots. The allergens identified in these patients had molecular weights distinct from those of known scorpion neurotoxins. A safe and effective skin testing extract can be prepared from dialyzed pure venom and may lead to the widespread ability to diagnose C. vittatus venom allergy.

Adult↗
PubMed1993

P05, a new leiurotoxin I-like scorpion toxin: synthesis and structure-activity relationships of the alpha-amidated analog, a ligand of Ca(2+)-activated K+ channels with increased affinity.

The venom of the scorpion Androctonus mauretanicus mauretanicus contains a toxin, P05, which is structurally and functionally similar to scorpion leiurotoxin I (87% sequence identity), a blocker of the apamin-sensitive Ca(2+)-activated K+ channels. It is a 31-residue polypeptide cross-linked by three disulfide bridges. A C-terminal carboxyl-amidated analog of P05 (sP05-NH2) was chemically synthesized by the solid-phase technique and fully characterized. Toxicity assays in vivo established that sP05-NH2, like native P05, is a potent and lethal neurotoxic agent in mice (LD50 of 20 ng per mouse). Pharmacological assays in vitro however showed that, unlike P05 which has a binding affinity of 2 x 10(-11) M, sP05-NH2 apparently binds irreversibly to the apamin receptor. Iodination at the C-terminal His gave diiodo-sP05-NH2, which had a binding affinity similar to that of native P05. The disulfide bridge pairings were chemically determined for sP05-NH2 and thereby deduced for P05 and leiurotoxin I: linkages were between Cys3 and Cys21, Cys8 and Cys26, and Cys12 and Cys28. Molecular dynamics refinement of P05 also using data from leiurotoxin I suggests that P05 is mainly composed of a double-stranded, antiparallel beta-sheet (from Leu18 to Val29) linked to an alpha-helix (from Arg6 to Gly16) by two disulfides (Cys8-Cys26 and Cys12-Cys28) and to an extended fragment (from Thr1 to Leu5) by the third disulfide (Cys3-Cys21). In agreement with the model, circular dichroism analysis of sP05-NH2 showed that the toxin structure is highly rigid.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1984

Binding of beta-scorpion toxin: a physicochemical study.

The binding to rat brain synaptosomes of a beta-scorpion toxin, i.e., toxin II of Centruroides suffusus suffusus (Css II), was studied as a function of pH, temperature, and concentration of some monovalent and divalent cations. At 10 degrees C and pH 6.0, the specific binding of 125I-labeled Css II corresponds to a single class of noninteracting high-affinity binding sites (KD = 0.18 nM) with a capacity (4.2 pmol/mg of protein) that is almost identical with that generally accepted for saxitoxin. The equilibrium dissociation constant of beta-scorpion toxin is pH independent, but the maximum binding capacity is reduced with increasing pH. Li+, guanidinium, Ca2+, Mg2+, and Mn2+ modified the apparent KD of the 125I-labeled Css II toxin. The equilibrium dissociation constant varies markedly with the temperature. The van't Hoff plot of the data is curvilinear, corresponding to a standard free-energy change associated with an entropy-driven process. The association rate constant also varies considerably with the temperature whereas the Arrhenius plot is linear between 1 and 30 degrees C. The energy of activation determined from these data is 17.6 kcal/mol. These results support the hypothesis that a cluster of nonpolar amino acid residues present on one face of the molecule is involved in the toxin-receptor interaction.

Animals↗
PubMed1986

Use of antibodies specific to defined regions of scorpion alpha-toxin to study its interaction with its receptor site on the sodium channel.

Five antibody populations selected by immunoaffinity chromatography for their specificity toward various regions of toxin II of the scorpion Androctonus australis Hector were used to probe the interaction of this protein with its receptor site on the sodium channel. These studies indicate that two antigenic sites, one located around the disulfide bridge 12-63 and one encompassing residues 50-59, are involved in the molecular mechanisms of toxicity neutralization. Fab fragments specific to the region around disulfide bridge 12-63 inhibit binding of the 125I-labeled toxin to its receptor site. Also, these two antigenic regions are inaccessible to their antibodies when the toxin is bound to its receptor site. In contrast, the two other antigenic sites encompassing the only alpha-helix region (residues 23-32) and a beta-turn structure (residues 32-35) are accessible to their respective antibodies when the toxin is bound to its receptor. Together, these data support the recent proposal that a region made of residues that are conserved in the scorpion toxin family is involved in the binding of the toxin to the receptor.

Amino Acid Sequence↗
PubMed1990

Neurotoxins active on insects: amino acid sequences, chemical modifications, and secondary structure estimation by circular dichroism of toxins from the scorpion Androctonus australis Hector.

Two scorpion neurotoxins active only on insects, the insect toxins AaH IT1 and AaH IT2, were purified from the venom of scorpions Androctonus australis Hector collected in Tozeur (Tunisia) and characterized. AaH IT2 was sequenced and found to differ in four amino acid positions from AaH IT, the single previously sequenced insect toxin [Darbon, H., Zlotkin, E., Kopeyan, C., Van Rietschoten, J., & Rochat, H. (1982) Int. J. Pept. Protein Res. 20, 320-330] which possessed an equal potential for paralyzing fly larvae. The basic amino acid residues of AaH IT1, which differs from AaH IT by one amino acid residue, were selectively chemically modified. Six derivatives were characterized. Their toxicity toward fly larvae and cockroach was determined, and their affinity for the AaH IT1 synaptosomal receptor from cockroach nerve cord was measured. Modification of His-30, Lys-34, and Arg-60 showed no significant effect on biological activity. However, the modification of Lys-28 or Lys-51 demonstrated that these two amino acids are important for toxicity. Furthermore, simultaneous modifications of both Lys-28 and Lys-51 led to a cumulative decrease in biological activity. AaH IT1 and AaH IT2 show similar CD spectra. The secondary structures content of AaH IT2 was estimated from circular dichroism data. Results showed that this class of toxin should possess an additional alpha-helical region and a beta-sheet strand, not found in toxins active on mammals. Attempts to localize these secondary structural features in the amino acid sequence of AaH IT2 indicated that these two regions would be located within the last 20 C-terminal amino acid residues. From these studies on secondary structures, it is possible to consider that toxins active on insects are more structurally constrained than those active on mammals; a decreased molecular flexibility may be, at least partially, responsible for the observed specificity of these toxins for the insect sodium channel. Furthermore, the two alpha-helices found in insect toxins enclosed the two conserved Lys-28 and Lys-51 and might thus be implicated in the toxic site of insect toxins.

Amino Acid Sequence↗
PubMed2004

Solution structure of BmKK4, the first member of subfamily alpha-KTx 17 of scorpion toxins.

BmKK4 is a 30 amino acid peptide purified from the venom of the Chinese scorpion Buthus martensi Karsch. It has been classified as the first member of scorpion toxin subfamily alpha-KTx 17. The 3D structure of BmKK4 in solution has been determined by 2D NMR spectroscopy. This toxin adopts a common alpha/beta-motif, but shows a distinctive local conformation. The most novel feature is that the regular arrangements of the side chains of the residues involved in the beta-sheet of BmKK4 are distorted by a classic beta-bulge structure, which involves two residues (Asp18 and Arg19) in the first strand opposite a single residue (Tyr26) in the second strand. The bulge produces two main changes in the structure of the antiparallel beta-sheet: (1) It disrupts the normal alteration of the side chain direction; the side chain of Asp18 turns over to form a salt bridge with that of Arg19. (2) It accentuates the twist of the sheet, and alters the direction of the antiparallel beta-sheet. The unusual structural feature of the toxin is attributed to the shorter peptide segment (Leu15-Arg19) between the third and fourth Cys residues and two unique residues (Asp18 and Arg19) at the position preceding the fourth Cys. In addition, the lower affinity of the peptide for the Kv channel is correlated to the structural features: residue Arg19 instead of a Lys residue at the critical position for binding and the salt bridge formed between residues Arg19 and Asp18.

Amino Acid Motifs↗
PubMed1997

A novel potassium channel blocking toxin from the scorpion Pandinus imperator: A 1H NMR analysis using a nano-NMR probe.

The three-dimensional solution structure of a novel peptide, Pi 1, purified from the venom of the scorpion Pandinus imperator and specific for potassium channels was determined by homonuclear proton NMR methods at 500 MHz from nanomole amounts of compound. P. imperator toxin is a voltage-dependent potassium channel specific peptide capable of blocking the shaker B K+ channels expressed in Sf9 cells in culture (Spodoptera frugiperda cell line no. 9) and displacing labeled noxiustoxin from rat brain synaptosomal membranes. The toxin has only 35 amino acid residues but is stabilized by four disulfide bridges (Cys4-Cys25, Cys10-Cys30, Cys14-Cys32, and Cys20-Cys35) instead of three commonly found in small potassium channel toxins. A detailed nuclear magnetic resonance structure of this protein was obtained using a nano-NMR probe and a combination of two-dimensional proton NMR experiments. The dihedral angles and distance restraints obtained from measured NMR parameters were used in structural calculations in order to determine the solution conformation of the toxin. The structure is organized around a short alpha-helix spanning residues Ser8-Thr18 and a beta-sheet. These two elements of secondary structure are stabilized by two disulfide bridges, Cys10-Cys30 and Cys14-Cys32. The antiparallel beta-sheet is composed of two strands extending from Asn22 to Cys32 with a tight turn at Arg28-Met29 in contact with the N-terminal fragment Leu1-Cys4. Comparison between the 3D structure of Pi 1 and those of other structurally and functionally related scorpion toxins is presented.

Amino Acid Sequence↗
PubMed2004

Morphofunctional changes in incubated Mauthner neurons in goldfish treated with peptides from scorpion venom.

Electron microscopy with negative contrast showed that direct interaction of one of the peptide fractions of scorpion venom with monomeric chromatographically pure actin led to polymerization of actin, transforming it from the globular form to the fibrillar form. The effects of prolonged orthodromic stimulation on the evoked electrical activity and ultrastructure of Mauthner neurons (MN) were studied in incubated slices of goldfish medulla oblongata in the presence of this actin-polymerizing venom fraction. Peptides in this fraction were found to stabilize the amplitude of the electrical response of MN to exhaustion and to protect the ultrastructure of afferent chemical synapses and the neurons themselves from damage induced by stimulation. Enhancements in morphofunctional resistance were accompanied by stabilization of actin-containing specialized synaptic structures--desmosome-like contacts. The data obtained here provide evidence that peptides of this fraction of scorpion venom have direct actions on the actin component of the MN cytoskeleton and demonstrate potential for its use as a pharmacological tool able to penetrate living cells with value for studying the role of actin in the mechanisms of adaptation and memory.

Animals↗
PubMed1999

Chemical synthesis and structure-activity relationships of Ts kappa, a novel scorpion toxin acting on apamin-sensitive SK channel.

Tityus kappa (Ts kappa), a novel toxin from the venom of the scorpion Tityus serrulatus, is a 35-residue polypeptide cross-linked by three disulphide bridges and acts on small-conductance calcium-activated potassium channels (SK channels). Ts K was chemically synthesized using the solid-phase method and characterized. The synthetic product, sTs kappa, was indistinguishable from the natural toxin when tested in vitro in competition assay with radiolabelled apamin for binding to rat brain synaptosomes (IC50 = 3 nM). The sTs kappa was further tested in vivo for lethal activity to mice following intracerebroventricular inoculation (LD50 = 70 ng per mouse). The half-cystine pairings were formerly established by enzyme-based cleavage of sTs kappa; they were between Cys7-Cys28, Cys13-CyS33 and Cys17-Cys35, which is a disulphide bridge pattern similar to that of other short scorpion toxins. According to previous studies on SK channel-acting toxins, the putative influence of certain basic residues of Ts kappa (i.e. Arg6, Arg9, Lys18, Lys19) in its pharmacological activity was investigated using synthetic point-mutated analogues of the toxin with an Ala substitution at these positions. Data from binding assay, together with conformational analysis of the synthetic analogues by 1H-NMR, suggest that Arg6, and to a lesser extent Arg9, are important residues for an high-affinity interaction of this toxin with SK channels; interestingly these residues are located outside the alpha-helical structure, whereas the pharmacologically important basic residues from other SK channel-specific toxins had been located inside the alpha-helix.

Amino Acid Sequence↗