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PubMed2002

Synthesis, 3-D structure, and pharmacology of a reticulated chimeric peptide derived from maurotoxin and Tsk scorpion toxins.

Maurotoxin (MTX) is a 34-mer scorpion toxin cross-linked by four disulfide bridges that acts on both Ca(2+)-activated (SK) and voltage-gated (Kv) K(+) channels. A 38-mer chimera of MTX, Tsk-MTX, has been synthesized by the solid-phase method. It encompasses residues from 1 to 6 of Tsk at N-terminal, and residues from 3 to 34 of MTX at C-terminal. As established by enzyme cleavage, Tsk-MTX displays half-cystine pairings of the type C1-C5, C2-C6, C3-C7 and C4-C8 which, contrary to MTX, correspond to a disulfide bridge pattern common to known scorpion toxins. The 3-D structure of Tsk-MTX, solved by (1)H NMR, demonstrates that it adopts the alpha/beta scaffold of scorpion toxins. In vivo, Tsk-MTX is lethal by intracerebroventricular injection in mice (LD(50) value of 0.2 microg/mouse). In vitro, Tsk-MTX is as potent as MTX, or Tsk, to interact with apamin-sensitive SK channels of rat brain synaptosomes (IC(50) value of 2.5 nM). It also blocks voltage-gated K(+) channels expressed in Xenopus oocytes, but is inactive on rat Kv1.3 contrary to MTX.

Amino Acid Sequence↗

PubMed1999

Crystal structure of neurotoxin Ts1 from Tityus serrulatus provides insights into the specificity and toxicity of scorpion toxins.

The crystal structure of neurotoxin Ts1, a major component of the venom of the Brazilian scorpion Tityus serrulatus, has been determined at 1.7 A resolution. It is the first X-ray structure of a highly toxic anti-mammalian beta-toxin. The folding of the polypeptide chain of Ts1 is similar to that of other scorpion toxins. A cysteine-stabilised alpha-helix/beta-sheet motif forms the core of the flattened molecule. All residues identified as functionally important by chemical modification and site-directed mutagenesis are located on one side of the molecule, which is therefore considered as the Na+channel recognition site. The distribution of charged and non-polar residues over this surface determines the specificity of the toxin-channel interaction. Comparison to other scorpion toxins shows that positively charged groups at positions 1 and 12 as well as a negative charge at position 2 are likely determinants of the specificity of beta-toxins. In contrast, the contribution of the conserved aromatic cluster to the interaction might be relatively small. Comparison of Ts1 to weak beta-toxins from Centruroides sculpturatus Ewing reveals that a number of basic amino acid residues located on the face of the molecule opposite to the binding surface may account for the high toxicity of Ts1.

Amino Acid Sequence↗

PubMed1997

In vitro folding and functional analysis of an anti-insect selective scorpion depressant neurotoxin produced in Escherichia coli.

The selective toxicity of depressant scorpion neurotoxins to insects is useful in studying insect sodium channel gating and has an applied potential. In order to establish a genetic system enabling a structure-activity approach, the functional expression of such polypeptides is required. By engineering the cDNA encoding the depressant scorpion neurotoxin, LahIT2, behind the T7 promoter, large amounts of recombinant insoluble and nonactive toxin were obtained in Escherichia coli. Following denaturation and reduction, the recombinant protein, constructed with an additional N-terminal methionine residue, was subjected to renaturation. Optimal conditions for reconstitution of a functional toxin, having a dominant fold over many other possible isoforms, were established. The recombinant active toxin was purified by RP-HPLC and characterized. Toxicity (ED50) to insects, binding affinity (IC50) to an insect receptor site, and electrophysiological effect on an insect axonal preparation were found to be similar to those of the native toxin. Substitution of the C-terminal glycine by a Gly-Lys-Lys triplet did not abolish folding but affected toxicity (3.5-fold decrease) of LqhIT2. Apparently, this efficient bacterial expression system (500 micrograms HPLC-purified toxin/1 liter E. coli culture) provides the means for studying structure/ activity relationship and the molecular basis for the phylogenetic selectivity of scorpion depressant neurotoxins.

Animals↗

PubMed1990

Voltage-sensitive Na+ channels in mammalian peripheral nerves detected using scorpion toxins.

The localization of voltage-sensitive sodium channels was investigated in mouse, rat and rabbit sciatic nerves using iodinated alpha- and beta-Scorpion toxins (ScTx) as specific probes. Saturable specific binding for a beta-ScTx was detected in mouse sciatic nerve homogenates (Kd = 90 pM, binding site capacity = 90 fmol mg-1 protein). LM autoradiographic studies demonstrated that the two types of ScTx stained the Ranvier nodes of the myelinated fibres, and also showed a clear but weaker labelling of the unmyelinated Remak bundles. In the sciatic nerve, which is widely considered as a model 'myelinated nerve', the nodal membrane represented only a small fraction of the total axonal membranes (0.2% and 0.05% for mouse and rabbit sciatic nerves respectively). Therefore, despite their high channel density, nodal membranes contribute only a small proportion of the total labelling by beta-ScTx (15% and 2.3% for mouse and rabbit sciatic nerves respectively), with the major contribution to labelling arising from unmyelinated axons. The distribution of specific binding sites for a beta-Scorpion toxin was then analysed in cross-sections of rabbit sciatic nerve at the EM level. The quantitative analysis of autoradiograms involved three methods, the 50% probability circle method, and two cross-fire analyses using either systematically distributed hypothetical sources or hypothetical sources only located on the plasma membranes of axons and of Schwann cells associated with unmyelinated Remak bundles. No specific beta-Scorpion toxin binding sites were detected at the plasma membrane of Schwann cells from either myelinated fibres or unmyelinated bundles, or at the internodal surface of myelinated axons. Sites were only detected at the surface of unmyelinated axons and at nodal axolemma. Their density in unmyelinated axons was found to be in the range of 1-6 per micron2 of plasma membrane surface area by combining quantitative EM autoradiography and stereological measurements.

Animals↗

PubMed2002

Value of the plasma protein and hemoglobin concentration in the diagnosis of pulmonary edema in scorpion sting patients.

OBJECTIVE: To investigate the value of measuring total plasma protein and hemoglobin concentrations for the diagnosis of pulmonary edema secondary to scorpion envenomation. DESIGN AND SETTING: Retrospective study over a 4-year period in the medical intensive care unit of a university hospital. PATIENTS: 67 patients older than 3 years admitted in the intensive care unit for scorpion envenomation and stratified into two groups according to the presence of pulmonary edema assessed by a medical committee that took into account clinical, radiological, and blood gas data at admission and after treatment. Total plasma protein and hemoglobin concentrations were analyzed separately. RESULTS: At admission all patients with and without pulmonary edema exhibited polypnea and tachycardia. The mean plasma protein and hemoglobin concentrations were higher in patients with pulmonary edema (74+/-6 and 14.2+/-2.0 g/dl, respectively) than in those without pulmonary edema (64+/-6 and 12.3+/-1.4 g/dl). After 24 h plasma protein and hemoglobin concentrations decreased in the pulmonary edema group (-11 and -1.9 g/dl) despite a negative fluid balance (-500 ml). A plasma protein concentration of 70 g/l or more predicted the presence of pulmonary edema with a sensitivity of 80% a specificity of 96%, a positive predictive value of 97%, and negative predictive value of 77%. CONCLUSIONS: In scorpion-envenomed patients with cardiorespiratory manifestations high plasma protein and hemoglobin concentrations suggest the presence of pulmonary edema.

Adolescent↗

PubMed1999

Inactivated state dependence of sodium channel modulation by beta-scorpion toxin.

We have examined the effects of a beta-scorpion toxin purified from the venom of the Venezuelan scorpion Tityus discrepans, TdVIII, on heterologously expressed rat skeletal muscle Na+ channels (rSkM1). TdVIII (100 nM) produced a leftward shift in the voltage dependence of activation and reduced the peak Na+ conductance of rSkM1 channels coexpressed with the rat brain beta1 subunit in Xenopus laevis oocytes, suggesting that TdVIII is a beta-scorpion toxin. These effects did not depend on the presence of the beta1 subunit. Modification of rSkM1 activation by TdVIII could be augmented by increasing the rate of stimulation (enhanced use-dependence). Shifts in channel activation were also enhanced by introducing conditioning pulses to -10 mV, and this enhancement increased with conditioning pulse duration. On the other hand, TdVIII did not affect the activation of fast-inactivation deficient mutant Na+ channels, I1303Q/ F1304Q/M1305Q. These results suggest that modulation of rSkM1 Na+ channel gating by TdVIII depends on the toxin interacting with the inactivated state of the alpha subunit.

Animals↗

PubMed1987

Purification and characterization of a beta-toxin from the venom of the African scorpion Leiurus quinquestriatus.

The venom of the African scorpion Leiurus quinquestriatus was subjected to high-performance ion-exchange chromatography. Among a large number (greater than 25) of small proteins and other substances, a protein component of approx. 6500 Da was purified. The effect of this toxin was tested on single myelinated nerve fibres of the frog Rana esculenta. Toxin concentrations less than 10 nM produced clear effects. Activation rather than inactivation of the voltage-dependent sodium channel was strongly affected. Thus, this toxin from an African scorpion acts like the beta-toxins present in the venom of North American scorpions.

Animals↗

PubMed1983

Effects of scorpion and rattlesnake venoms on the canine pancreas following pancreaticoduodenal arterial injections.

Three scorpion venoms caused a transitory decrease in the rate of fluid secretion and increases in the concentration, in pancreatic juice, of total protein and individual enzymes. Protein and enzyme elevations 4-7 fold over the basal levels were produced by the venom of Tityus bahiensis and 6-7 fold by venoms from Tityus serrulatus and Buthus quinquestriatus. Although these increases were smaller than those stimulated by the C-terminal octapeptide of cholecystokin (OP-CCK; 8-9 fold), the secretory responses were of longer duration, so that the total output of protein caused by each of the three venoms was significantly greater than that observed with OP-CCK. Although electron microscopy revealed evidence of widespread degeneration of acinar cells at 1 hr and more extensive damage at 2 hr following injection of scorpion venom, no free protease was detected in pancreatic secretion collected during this period. The scorpion venoms also caused hypersecretion of viscid saliva. In contrast, rattlesnake venom, had no detectable effect on salivation, pancreatic secretion or morphology of the pancreas.

Animals↗

PubMed1988

Respiratory failure in children following envenomation by the scorpion Leiurus quinquestriatus: hemodynamic and neurological aspects.

Nine children, hospitalized for severe respiratory failure following scorpion envenomation, were a part of a group of 61 youngsters and infants admitted to the Pediatric Intensive Care Unit of the Soroka Medical Center, Beer-Sheva during the years 1983-87 because of scorpion venom intoxication. Four out of the nine had cardiogenic shock, three had severe systemic hypertension and one had severe airway obstruction. All nine patients had central nervous system manifestations, including lethargy, confusion and agitation (three cases), and markedly reduced level of consciousness (six cases). Hemodynamic studies performed in two patients showed 'high pressure' (cardiogenic) pulmonary edema. Seven patients recovered completely, one died and another one was left severely handicapped. Hydralazine i.v. showed a remarkable effect on the systemic blood pressure and central nervous system disturbances in addition to mechanical ventilation. Based on our own experience and previous clinical and experimental studies, the possible pathogenetic mechanisms underlying the respiratory and central nervous system dysfunction following scorpion sting are discussed.

Adolescent↗

PubMed1988

Amino acid sequence and physiological characterization of toxins from the venom of the scorpion Centruroides limpidus tecomanus Hoffmann.

The complete amino acid sequence of the major toxic component (II.20.3.4), named toxin 1, from the venom of the Mexican scorpion C. l. tecomanus is reported. The sequence (66 amino acids) was obtained by direct Edman degradation of reduced and alkylated toxin, followed by sequence determination of selected peptides separated after enzymatic cleavage with S. aureus V8 protease. In cultured chick dorsal root ganglion cells, 0.5 microM toxin 1 slowed down specifically the time course of Na+ current inactivation, while Ca2+ currents from the same preparation were little affected. In neonatal rat ventricular heart cells, toxin 1, at concentrations between 0.1 and 0.5 microM, reduced Na+ currents without changing the kinetics and Ca2+ currents were unaffected. Comparative analysis of the primary structure of this toxin with other scorpion toxins shows a high degree of similarity with the north American scorpion toxins. This analysis suggests that the 'fine tuning' of the molecular mechanism of action of these toxins is related to variations in the primary structure as well as to the type of membrane under study (tissue specificity).

Action Potentials↗

PubMed1990

Echocardiographic and radionuclide angiographic observations following scorpion envenomation by Leiurus quinquestriatus.

The echocardiographic and radionuclide angiographic abnormalities in children after scorpion envenomation with L. quinquestriatus, were evaluated. Five children were severely hypertensive, one of them in respiratory failure and another had pulmonary edema. The results revealed poor global contractility 12-15 hr after the sting in three patients. The radionuclide angiograms also revealed poor contractility with low ejection fraction. There was enzymatic evidence of myocardial damage. The changes observed in the echocardiograms and radionuclide angiograms were attributed to catecholamine induced myocardial ischemia. The abnormalities observed suggest that systolic dysfunction plays a role in the pathogenesis of heart failure in scorpion envenomation, in addition to a decrease of left ventricular compliance and increased impedance to left ventricular emptying. The beneficial effects of nifedipine in hypertension and other cardiovascular manifestations justify the routine use of afterload reduction in children with cardiovascular manifestations after scorpion envenomation.

Adolescent↗

PubMed1990

Structure-activity relationships of scorpion alpha-neurotoxins: contribution of arginine residues.

The role of arginine residues in the structure-activity relationships of alpha-scorpion neurotoxins was studied. Toxins I and II from Androctonus australis Hector (north African scorpion), containing respectively 2 and 3 arginines, were modified by phenylglyoxal or p-hydroxyphenylglyoxal. Modified derivatives were purified by reverse-phase HPLC and/or ion exchange HPLC. Subsequent bioassays showed that toxin I (AaH I) derivatives with single modifications on Arg 2 and Arg 60 had low activity (25 and 14% of residual activity, assessed in receptor binding experiments). Doubly modified (Arg 2, Arg 60) AaH I had 7% residual activity while further derivatization of the alpha-amino group led to an almost inactive derivative. These results agree with the involvement of arginines 2 and 60, as well as the alpha-amino group, of AaH I in the toxin/receptor interaction, probably via electrostatic interactions. Consistent with the role of N-terminal residues, the selective removal of the N-terminal dipeptide Val-Arg of toxin III from the same scorpion resulted in low activity (7% residual activity). The arginine residue in position 56 of toxin II was important for bioactivity since the derivative modified by phenylglyoxal on Arg 56 exhibited low residual activity (20%). Arg 62 and Arg 18, on the other hand, can be modified without any great effect on the pharmacological activity of AaH II. These results furnish a more precise picture of those residues involved in the "toxic region", which appears to be composed of residues belonging to the conserved hydrophobic surface and to the C-terminal and N-terminal sequences.

Amino Acid Sequence↗

PubMed1991

Myocardial injury without heart failure following envenomation by the scorpion Leiurus quinquestriatus in children.

The enzymatic activity of creatine kinase-MB isoenzyme (CK-MB), a sensitive and specific marker of myocardial damage, was measured in 32 children following scorpion envenomation. CK-MB activity, total creatine phosphokinase (CPK) and serum glutamine oxalacetic transaminase (SGOT) levels were examined for relationship with electrocardiographic (ECG) results and the clinical state of the children. Twenty-seven out of the 32 children had signs of systemic intoxication ("symptomatic" cases), while the other five children had only local signs ("asymptomatic" cases). Thirteen out of the 27 symptomatic children had enzymatic myocardial involvement characterized by high total CPK level, elevated CK-MB level and a CK-MB/CK ratio exceeding 6%. Six of these 13 children had ECG changes consistent with myocardial damage, and only one child had clinical signs of myocardial injury. None of the asymptomatic children, nor five healthy control children, had any evidence of myocardial damage as judged by CK-MB levels, clinical signs and ECG. Our study suggests that CK-MB activity is specific and highly sensitive in detecting myocardial damage in children following scorpion envenomation, and appears superior to ECG and clinical parameters. We speculate that the myocardial lesions are too small to cause heart failure in most cases, but they may account for the cardiovascular changes frequently seen in scorpion envenomation.

Adolescent↗

PubMed1993

Toxicity of scorpion (Buthus tamulus) venom in mammals is influenced by the age and species.

The present study was undertaken to determine the toxicity of scorpion (Buthus tamulus) venom in young and adult rats, as well as in different species of adult animals (rats, mice and guinea-pigs). The median lethal dose (LD50; mg/kg s.c.) of scorpion venom in young and adult rats was 2.2 +/- 0.21 and 1.3 +/- 0.14, respectively. The LD50 value for mice (7.2 +/- 1.35) was significantly greater than adult rats or guinea-pigs (1.14 +/- 0.08). The LD50 dose for i.v. route in anaesthetized adult rats was 95 +/- 13.2 micrograms/kg weight, which is 13 times less than that required for s.c. route. The results show that the lethality of scorpion venom in mammals differs with the age and species of the animals.

Aging↗

PubMed1995

Structure-activity studies on scorpion toxins that block potassium channels.

Scorpion venoms contain toxins that block different types of potassium channels. Some of these toxins have affinity for high conductance Ca(2+)-activated K+ channels and for dendrotoxin-sensitive voltage-dependent K+ channels. The structural features that determine the specificity of binding to different channel types are not known. We investigated this using natural and synthetic scorpion toxins. We have tested the effects of charybdotoxin (CTX) and two homologues (Lqh 15-1 and Lqh 18-2), iberiotoxin (IbTX), and kaliotoxin (KTX) from the scorpions Leiurus quinquestriatus hebreus, Buthus tamulus and Androctonus mauretanicus mauretanicus, respectively, and synthetic variants of CTX, namely CTX2-37, CTX3-37, CTX4-37, and CTX7-37, on a Ca(2+)-activated K+ current (IK-Ca) at a mammalian motor nerve terminal, and on the binding of a radiolabelled dendrotoxin, 125I-DpI, to voltage-dependent K+ channels on rat brain synaptosomal membranes. The native toxins contain 37-38 amino acid residues, they are over 30% identical in sequence (CTX and IbTX are 68% identical), and they have similar three-dimensional conformations. All toxins, except IbTX, displaced 125I-DpI from its synaptosomal binding sites: Lqh 18-2 (Ki = 0.25 nM), KTX (Ki = 2.1 nM), CTX (Ki = 3.8 nM), CTX2-37, (Ki = 30 nM), Lqg 15-1 (Ki = 50 nM), CTX3-37 (Ki = 60 nM), CTX4-37 (Ki = 50 nM), CTX7-37 (Ki = 105 nM). IbTX had no effect at 3 microM. When variants of CTX with deletions at the N-terminal portion were tested for their activity on IK-Ca on motor nerve terminals in mouse triangularis sterni nerve-muscle preparations, CTX3-37 and CTX4-37 were ineffective at 100 nM; and CTX7-37 was ineffective at up to 1 microM. IbTX and CTX (100 nM) completely blocked IK-Ca, but KTX (100 nM) did not affect the nerve terminal IK-Ca. Different residues appear to be important for interactions of the toxins with different K+ channels. IbTX did not displace dendrotoxin binding, but it did block IK-Ca, whereas KTX was as active as CTX against dendrotoxin binding but it did not affect the IK-Ca of the motor nerve terminals. The N-terminal section of the toxins appears to be particularly involved in block of IK-Ca at the motor nerve terminal: it is truncated in the inactive synthetic CTX variants; and it is positively charged at lysine-6 in KTX (which is inactive), but negatively charged in IbTX and neutral in CTX.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1994

Children with adrenergic manifestations of envenomation after Tityus serrulatus scorpion sting are protected from early anaphylactic antivenom reactions.

The incidence of early anaphylactic reactions to scorpion antivenom given i.v. after Tityus serrulatus scorpion sting was evaluated in 103 children aged up to 15 years in Belo Horizonte, Brazil. Patients without adrenergic manifestations (Group 1, n = 28) were compared with those who presented systemic involvement that included adrenergic manifestations (Group 2, n = 75). Data were recorded on a proforma and the presence or absence of early anaphylactic reaction was cross-tabulated according to clinical features, sex, age and volume of antivenom used in the treatment. Unpaired Student's t-test was used to calculate significance of differences in age and volume of antivenom used. Multivariate logistic regression was used to determine the effects of clinical features and volume of antivenom as predictors of early anaphylactic reaction to antivenom treatment. Twelve (42.9%) of 28 children included in Group 1 presented early anaphylactic reactions compared with 6 (8%) of 75 children of Group 2 (OR = 8.63; 95% CI: 2.88, 25.7). The reactions were more severe in Group 1. There were no significant differences with respect to age and sex. After adjusting for clinical form, volume of antivenom was not significantly associated with presence of reactions (OR = 1.11; 95% CI: 0.70, 2.80 for each 5.0 ml of antivenom administered). The results show that children with adrenergic manifestations after T. serrulatus scorpion sting had significantly lower anaphylactic reactions to antivenom than those without these manifestations.

Anaphylaxis↗

PubMed1994

Isolation and characterization of a novel toxin from the venom of the scorpion Centruroides limpidus limpidus Karsch.

A novel peptide, toxic to mice, was purified from the venom of the Mexican scorpion Centruroides limpidus limpidus, by means of gel filtration and ion exchange chromatography, followed by high performance liquid chromatography (HPLC). The complete amino acid sequence was determined by automatic Edman degradation of reduced and alkylated toxin, and by overlapping sequences of fragments of the toxin, generated by cleavage with proteinase V8 separated by HPLC. This toxin is composed of 66 amino acid residues, contains eight half-cystine residues, and is highly similar (91%) to the amino acid sequence deduced for toxin 1 of C. limpidus tecomanus and toxin 4 from C. noxius venom (89%). This peptide displaces the binding of radiolabeled toxin 2 of C. noxius from synaptosomal membranes of rat brain with superimposable kinetics, supporting the conclusion that it belongs to the beta-scorpion toxin class. Further characterization of C. l. limpidus toxin 1, as we have named it, was performed by means of competition experiments with monoclonal antibodies and various purified scorpion toxins, using an ELISA assay. A panel of six distinct monoclonal antibodies (mAB) against toxin 2 and 3 of C. noxius was used. From these, only three clones, originally named BCF1, BCF8 and BCF9, were able to recognize toxin 1 from C. l. limpidus.

Amino Acid Sequence↗

PubMed1996

Pharmacokinetics of Tityus serrulatus scorpion venom determined by enzyme-linked immunosorbent assay in the rat.

Experiments were performed in two groups of anaesthetized rats to study the genesis of pulmonary oedema and to determine the pharmacokinetic parameters following a subcutaneous (s.c.) injection of Tityus serrulatus scorpion venom. In group I, the rats were anaesthetized with pentobarbital (4 mg/100 g, i.p.); the s.c. injection of scorpion venom at the dose of 50 micrograms/100 g did not induce arterial hypertension, but unilateral pulmonary oedema was observed in three of six rats. The injection of a higher dose of venom (200 micrograms/100 g, N = 6) induced arterial hypertension and bilateral (N = 3) or unilateral (N = 1) pulmonary oedema. These data indicate that it is possible to evoke unilateral pulmonary oedema without previous arterial hypertension induced by the venom. For the study of pharmacokinetic parameters a second group of six rats was anaesthetized with urethane (140 mg/ 100 g, i.p.) and the venom injected at a dose of 200 micrograms/100 g, s.c. The plasma concentrations of venom were determined by enzyme-linked immunosorbent assay, at times 0, 5, 30, 60, 180, 360, and 720 min after venom injection. A biphasic curve was obtained with an ascending phase followed by a descending phase. The maximum plasma scorpion venom concentration was reached at 60 min. The pharmacokinetic parameters showed a fast absorption rate (Ka = 0.058 min-1), a fast and high distribution of venom to tissues (t1/2 alpha = 31.50 min and Vdarea = 6800.47 ml.kg-1, respectively), a great affinity of the venom for the tissues (KCT = 0.056 min-1 and KTC = 0.002 min-1) and a slow elimination half-life (t1/2 beta = 173.25 min).

Analysis of Variance↗