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PubMed2006

Adjusting force distributions in functional site of scorpion toxin BMK M1 by cooperative effect of disulfide bonds.

We decided to investigate the influence of the presence of disulfide bonds on the pattern of force distribution in the functional site of scorpion toxin BMK M1 in its functional state. Therefore, a series of short time molecular dynamics (MD) simulations were performed on this toxin in the native state and disulfide bond broken states. The comparison of disulfide bond broken states with the native state showed that the electrostatic potential energy of important functional residues in the reverse turn and C-terminal regions were modulated by the cooperative effect of all disulfide bonds in the molecule. Furthermore, our results revealed that disulfide bonds also play a cooperative role in modulating (1) the amplitude of the fluctuations of the functional segments and (2) the correlation of motions between important functional residue pairs in this toxin. Therefore, we can conclude that the disulfide bonds have cooperation to adjust the pattern of force distribution in the functional site of this toxin in its functional state.

Animals↗
PubMed2006

Scorpion digestive lipase: a member of a new invertebrate's lipase group presenting novel characteristics.

Unlike classical digestive lipases, the scorpion digestive lipase (SDL) has a strong basic character. The SDL activity's optimal pH, when using tributyrin or olive oil as substrate, was 9.0. Added to that, the estimated isoelectric point of the native SDL using the electrofocusing technique, was found to be higher than 9.6. To our knowledge, this is the first report of an animal digestive lipase having such a basic character. When olive oil was used as substrate, SDL was shown to be insensitive to the presence of amphiphilic proteins such as bovine serum albumin (BSA). Furthermore, the hydrolysis was found to be specifically dependent on the presence of Ca(2+) ions, since no significant SDL activity was detected in the presence of ions chelator such as EDTA. Nevertheless, the SDL does not require Ca(2+) to trigger the hydrolysis of tributyrin emulsion. Interestingly Zn(2+) and Cu(2+) ions act as strong inhibitors of SDL activity when using tributyrin as substrate. An internal chymotryptic cleavage of SDL generated two fragments of 28 and 25 kDa having the same N-terminal sequence. This sequence of 19 residues does not share any homology with known animal and microbial lipases. Polyclonal antibodies directed against SDL (pAbs anti-SDL) failed to recognise ostrich pancreatic and dog gastric lipases (OPL and rDGL). Moreover, both pAbs anti-OPL and anti-rDGL failed to immunoreact with SDL. These immunological as well as distinct biochemical properties strengthen the idea that SDL appears to belong to a new invertebrate's lipase group.

Animals↗
PubMed2003

TSII toxin isolated from Tityus serrulatus scorpion venom: behavioral, electroencephalographic, and histopathologic studies.

We have reported earlier that intrahippocampal administration of the C-pool from Tityus serrulatus scorpion venom induces convulsions in rats. Here we report the effects of seven toxins isolated from the C-pool. The strongest effects were seen after toxin 5C, which was sequenced and identified as TSII, a beta-type toxin that affects Na+ channel activation. Unilateral injection of TSII in the rat hippocampus (1.7 microg/microl) induced clusters of spikes and epileptic discharges of mainly moderate intensity, convulsion-related behavioral changes (wet dog shakes, staring, masticatory jaw movements, facial automatisms, orofacial movements, intense sniffing, blinking, and forelimb clonus with rearing and falling) and a massive neuronal loss of pyramidal cells in the ipsilateral CA1, CA3, and CA4 subfields and of granulate cells of the ipsilateral dentate gyrus. Toxins C3, C4, and C6 induced weaker changes in the EEG and behavioral changes and failed to induce cell death, and toxins C1, C2, and C7 had no effects. The similarities in the effects of TsTx, a alpha-type toxin that affects Na+ channel, suggest that the loss of modulation of activation of the sodium channel caused by TSII increases glutamate release, leading to long-lasting increases in intracellular Ca2+ and cell death.

Amino Acid Sequence↗
PubMed2006

Estrogen modulates in vitro atrial bradycardia induced by Indian red scorpion venom via G-protein coupled mechanisms.

Role of estrogen on cardiac dysrhythmia produced by Indian red scorpion (Mesobuthus tamulus) venom was examined using rat right atrial preparations in vitro. In females, the M. tamulus venom produced an increase, a decrease and an increase in rate at 0.03, 0.3 and 3 microg/ml of venom, respectively, producing N-shaped response curve, whereas no such response pattern was observed in males. Force of contraction in females was increased at all the concentrations of the venom, while in males the increase was seen only at 3 microg/ml. Castration of male rats did not alter the venom response to female type, while 'estrogenisation of castrated male rats' (pseudofemales) produced a response similar to females. Tamoxifen reversed the venom-induced responses both in females and pseudofemales. Further in females, the venom action at 0.3 microg/ml was blocked by atropine. Response at this concentration was also blocked by pertussis toxin and methylene blue. Results suggest that the cholinergic component of venom response is modulated by estrogen receptors via G(i)-protein-guanylyl cyclase mechanism.

Animals↗
PubMed2006

The first potassium channel toxin from the venom of the Iranian scorpion Odonthobuthus doriae.

The very first member of K(+) channels toxins from the venom of the Iranian scorpion Odonthobuthus doriae (OdK1) was purified, sequenced and characterized physiologically. OdK1 has 29 amino acids, six conserved cysteines and a pI value of 4.95. Based on multiple sequence alignments, OdK1 was classified as alpha-KTx 8.5. The pharmacological effects of OdK1 were studied on six different cloned K(+) channels (vertebrate Kv1.1-Kv1.5 and Shaker IR) expressed in Xenopus laevis oocytes. Interestingly, OdK1 selectively inhibited the currents through Kv1.2 channels with an IC50 value of 183+/-3 nM but did not affect any of the other channels.

Animals↗
PubMed2004

Bone marrow-derived mast cells in mice respond in co-culture to scorpion venom activation of superior cervical ganglion neurites according to level of expression of NK-1 receptors.

In virtually all tissues of the body, mast cells are closely associated with nerve fibers, mostly of sensory origin. While mast cells can be activated by substance P, evidence for the involvement of NK-1 receptors is very limited. To study functional interactions between mast cells and peripheral nerves, bone marrow-derived mast cells (BMMC) and superior cervical ganglia (SCG) were co-cultured. Murine bone marrow-derived mast cells are homologues for mucosal mast cells and have recently been shown to express NK-1 receptors. Bi-directional interaction was studied using a fluorescent calcium indicator as an index of cellular activation. Scorpion venom, not affecting BMMC by itself, caused a rapid increase in neurite fluorescence subsequently followed by activation of the mast cell. The latter was inhibited by the NK-1 receptor antagonist SR140333, showing the direct involvement of substance P and its receptor in this co-culture system. Activation of BMMC seemed to be directly correlated with extent of NK-1 receptor expression. Immature c-kit positive cells not expressing NK-1 gave a negligible response to neurite activation. In addition, there was a maximum stimulation occurring when NK-1 expression exceeded 16% on BMMC after cytokine stimulation. Our findings show that the expression of NK-1 receptors appears to be important for nerve-mast cell communication.

Animals↗
PubMed2004

Expression and purification of the BmK Mm2 neurotoxin from the scorpion Buthus martensii Karsch and its biological activity test.

The gene encoding neurotoxin (BmK Mm2) from the scorpion Buthus martensii Karsch was expressed in Escherichia coli BL21 (DE3) at a level of 1.6 mg/L using expression plasmid pExSecI system. SDS-PAGE analysis of the cell lysate confirmed that gene BmK Mm2 was expressed in soluble form and the expressed production was secreted into Luria-Bertani (LB) culture medium from Escherichia coli. According to the characters of pExSecI expression system, the IgG binding domain-ZZ of Protein A is fused to the N-terminal of BmK Mm2. Recombinant BmK Mm2 (ZZ-BmK Mm2, pI 6.81, 22.007 kDa) was purified rapidly and efficiently by IgG-Sepharose 6 Fast Flow and Superdex-75 gel filtration chromatography, produced a single band on SDS-PAGE. Western blot analysis demonstrated that this protein was recombinant BmK Mm2. The results of MTT assay, morphological observation of nucleus and single cell gel electrophoresis showed that the expressed recombinant BmK Mm2 was toxic for glial cells of mice, which indicate that it has biological activity.

Animals↗
PubMed2005

Scorpion-toxin mimics of CD4 in complex with human immunodeficiency virus gp120 crystal structures, molecular mimicry, and neutralization breadth.

The binding surface on CD4 for the HIV-1 gp120 envelope glycoprotein has been transplanted previously onto a scorpion-toxin scaffold. Here, we use X-ray crystallography to characterize atomic-level details of gp120 with this transplant, CD4M33. Despite known envelope flexibility, the conformation of gp120 induced by CD4M33 was so similar to that induced by CD4 that localized measures were required to distinguish ligand-induced differences from lattice variation. To investigate relationships between structure, function, and mimicry, an F23 analog of CD4M33 was devised. Structural and thermodynamic analyses showed F23 to be a better molecular mimic of CD4 than CD4M33. F23 also showed increased neutralization breadth, against diverse isolates of HIV-1, HIV-2, and SIVcpz. Our results lend insight into the stability of the CD4 bound conformation of gp120, define measures that quantify molecular mimicry as a function of evolutionary distance, and suggest how such evaluations might be useful in developing mimetic antagonists with increased neutralization breadth.

Animals↗
PubMed2006

Effects of Tityus serrulatus scorpion venom and its toxin TsTX-V on neurotransmitter uptake in vitro.

Scorpion neurotoxins targeting the Na(v) channel can be classified into two classes: alpha- and beta-neurotoxins and are reported as highly active in mammalian brain. In this work, we evaluate the effects of Tityus serrulatus venom (Ts venom) and its alpha-neurotoxin TsTX-V on gamma-aminobutyric acid (GABA), dopamine (DA) and glutamate (Glu) uptake in isolated rat brain synaptosomes. TsTX-V was isolated from Ts venom by ion exchange chromatography followed by reverse-phase (C18) high-performance liquid chromatography. Neither Ts venom nor TsTX-V was able to affect (3)H-Glu uptake. On the other hand, Ts venom (0.13 microg/mg) significantly inhibited both (3)H-GABA and (3)H-DA uptake ( approximately 50%). TsTX-V showed IC(50) values of 9.37 microM and 22.2 microM for the inhibition of (3)H-GABA and (3)H-DA uptake, respectively. These effects were abolished by pre-treatment with tetrodotoxin (TTX, 1 microM), indicating the involvement of voltage-gated Na(+) channels in this process. In the absence of Ca(2+), and at low Ts venom concentrations, the reduction of (3)H-GABA uptake was not as marked as in the presence of Ca(2+). TsTX-V did not reduce (3)H-GABA uptake in COS-7 cells expressing the GABA transporters GAT-1 and GAT-3, suggesting that this toxin indirectly reduces the transport. The reduced (3)H-GABA uptake by synaptosomes might be due to rapid cell depolarization as revealed by confocal microscopy of C6 glioma cells. Thus, TsTX-V causes a reduction of (3)H-GABA and (3)H-DA uptake in a Ca(2+)-dependent manner, not directly affecting GABA transporters, but, in consequence of depolarization, involving voltage-gated Na(+) channels.

Animals↗
PubMed2005

The role of voltage-gated Na+ channels in excitation-contraction coupling of rat heart determined by BmK I, an alpha-like scorpion neurotoxin.

A mechanism underlying the increase in rat heart contractility modulated by BmK I, an alpha-like scorpion neurotoxin, was investigated using whole-cell patch-clamp and fluorescence digital imaging techniques. Results showed that (a) L-type Ca2+ current could not be modified by 500 nM BmK I; (b) The inactivation process of Na+ current was significantly delayed with no change of its amplitude; (c) The overall intracellular Na+ and Ca2+ concentration could be augmented in the presence of BmK I; (p<0.05); (d) The increase of free intracellular Ca2+ concentration induced by BmK I was inhibited completely by 5 mM NiCl2 (p<0.05), an inhibitor of Na+-Ca2+ exchanger; (e) The spontaneous Ca2+ release induced by 10 mM caffeine from sarcoplasmic reticulum could not be modulated by 500 nM BmK I in the absence of external Ca2+. These results indicate that cardiac voltage-gated Na+ channels are also targets of BmK I. Na+ accumulation through Na+ channels can trigger sarcoplasmic reticulum Ca2+ release in rat cardiac myocytes via reverse-mode Na+-Ca2+ exchanger. Furthermore, Ca2+ release from sarcoplasmic reticulum induced by BmK I most likely involves a Ca2+-induced release mechanism.

Animals↗
PubMed2004

Isolation, molecular cloning and functional characterization of a novel beta-toxin from the Venezuelan scorpion, Tityus zulianus.

Sting in children by Tityus zulianus scorpions (western Venezuela) often produces cardiorespiratory arrest and death by pulmonary oedema. To assess its toxicity, lethality in mice of T. zulianus soluble venom was determined. Toxin composition was studied by fractionating the crude venom through reversed-phase HPLC. The most abundant peptide, Tz1, was purified further and its N-terminal sequence, amino acid composition and molecular mass (by electron-spray ionization mass spectrometry) determined. In the presence of Tz1, activation of recombinant rat skeletal muscle sodium channels (Na(V)1.4) was shifted about 35 mV in the hyperpolarizing direction in a prepulse-dependent manner. This typical beta-toxin effect had an apparent EC50 of 3.5 microM A cDNA sequence encoding Tz1 was isolated from T. zulianus venom gland RNA using a combination of 5'- and 3'-RACE PCR. Analysis of the encoded sequence indicated that Tz1 is the processed product of a precursor containing: (i) a 20-residue long leader peptide; (ii) the amino acid sequence of the mature toxin (64 residues); and (iii) an extra Gly-Lys tail at the C-terminus, probably removed post-translationally. A comparison of Tz1 with Tityus serrulatus beta-toxin Ts1 revealed that some of the non-conservative replacements in Tz1 lie in regions potentially involved in receptor recognition.

Animals↗
PubMed2004

Histopathological changes and inflammatory response induced by Tityus discrepans scorpion venom in rams.

Anesthetized rams envenomed s.c. with 40 microg/kg Tityus discrepans scorpion venom developed fasciculation, hypothermia, polyuria, pulmonary wet rales, tachypnea, respiratory distress and arrhythmia. Rams developed a cascade of inflammation reactions, characterized by activation of macrophages, fibroblasts and neutrophils, neutrophil infiltration and aggregation, vasculitis, arteritis and abundant fibrin deposition. At the inoculation site, venom was detected by immunohistochemistry in the extra cellular matrix, lymphatic vessels' and venules' lumen, inside macrophages and surrounding nerves. Extra cellular matrix was degraded at the inoculation site perhaps by activated neutrophils. Envenoming produced hepatocytes with Mallory body-like vacuoles which may be due to the increased plasmatic levels of TNF-alpha and IL6. Venom produced degranulation and vacuolization of acinary cells as well as interstitial swelling and necrosis. Necrosis of the Langerhan's islets occurred occasionally. Lungs showed the most deleterious effects developing wall collapse and necrosis, diffuse injury of the alveolar capillary barrier, interstitial and alveolar fibrin deposits with strong neutrophil infiltration. Massive infiltration of lymphocytes and macrophage occurred in the intestinal submucose, to the point that it modified villi and intestinal folding morphology. Envenomation developed a marked leukocyte aggregation surrounding nerves at the inoculation site. This study reveals that beyond its neurotoxicity, Tityus venom produces a severe and widespread inflammatory syndrome, expressed as histopathological changes at the site of inoculation, as well as in remote organs such as pancreas, lungs, intestine and liver. Our results suggest that not all remote targets are directly affected by the venom but that, as proposed earlier, are modified by inflammation by products produced elsewhere.

Animals↗
PubMed2006

Depression of cardiac L-type calcium current by a scorpion venom fraction M1 following muscarinic receptors interaction involving adenylate cyclase pathway.

The effects of a non-toxic fraction, called M1, from Buthus occitanus tunetanus (Bot) scorpion were studied on rat cardiac contraction and calcium transient and current. A decrease in both rate and tension on isolated intact hearts as well as in calcium transient induced by depolarizing 100 K(+) solution on isolated ventricular cardiomyocytes was firstly observed. Studies with the whole cell patch clamp method showed that M1 decreased the L-type calcium current (ICa(L)) in a dose-dependent manner with an IC50 of 0.36 microg/mL and a Hill coefficient of 0.95. This effect was blocked and reversed by the specific muscarinic receptors antagonist atropine, 1 microM, and was completely prevented when cardiomyocytes were pretreated with Pertussis toxin, 1 microg/mL, to block the alpha subunit of the PTX-sensitive G proteins. These results show that M1 fraction of Bot inhibits basal calcium current by interacting with muscarinic receptors and suggest that this inhibition could be attributed to inhibition of adenylate cyclase activity by a mechanism involving PTX-sensitive G proteins.

Adenylyl Cyclase Inhibitors↗
PubMed1999

Effects of crude venom, tityustoxin and toxin Ts-gamma from Tityus serrulatus scorpion on secretion and structure of the rat submandibular gland.

Changes in the rat submandibular glands after intravenous injections of Tityus serrulatus scorpion venom, tityustoxin or toxin Ts-gamma were studied histologically and morphometrically. The acini and the granular convoluted tubules presented the most prominent changes. The following variables were measured: (a) relative volume occupied by the glandular structures; (b) diameter of the granular convoluted tubules and thickness of their epithelium; (c) diameter of the acini. The cytoplasm of the acinar cells was extensively occupied by large confluent vacuoles and had a reduced number of secretory granules after intravenous injections of venom or toxins. The morphological changes caused by toxin Ts-gamma were greater than those evoked by tityustoxin or crude venom injections. In spite of the changes in acinar cells, acinar diameter showed no significant alterations after venom or toxin injections. Reduction of diameter and depletion of the cytoplasmic secretory granules were observed in the granular convoluted tubules 2 h after intravenous injections of crude venom, or after 1 h with tityustoxin or toxin Ts-gamma. The intravenous injection of crude venom did not induce any visible change in the granular convoluted tubules after 1 h. These structural changes could explain the concomitant intense sialagogue effect elicited by crude venom, tityustoxin and toxin Ts-gamma. The sialagogue effect induced by toxin Ts-gamma was larger than those induced by crude venom or tityustoXin.

Animals↗
PubMed2000

Fast K(+) currents from cerebellum granular cells are completely blocked by a peptide purified from Androctonus australis Garzoni scorpion venom.

A novel peptide was purified from the venom of the scorpion Androctonus australis Garzoni (abbreviated Aa1, corresponding to the systematic number alpha KTX4.4). It contains 37 amino acid residues, has a molecular mass of 3850 Da, is closely packed by three disulfide bridges and a blocked N-terminal amino acid. This peptide selectively affects the K(+) currents recorded from cerebellum granular cells. Only the fast activating and inactivating current, with a kinetics similar to I(A)-type current, is completely blocked by the addition of low micromolar concentrations (K(i) value of 150 nM) of peptide Aa1 to the external side of the cell preparation. The blockade is partially reversible in our experimental conditions. Aa1 blocks the channels in both the open and the closed states. The blockage is test potential independent and is not affected by changes in the holding potential. The kinetics of the current are not affected by the addition of Aa1 to the preparation; it means that the block is a simple 'plugging mechanism', in which a single toxin molecule finds a specific receptor site in the external vestibule of the K(+) channel and thereby occludes the outer entry to the K(+) conducting pore.

Amino Acid Sequence↗
PubMed2003

Scorpion toxins that block T-type Ca2+ channels in spermatogenic cells inhibit the sperm acrosome reaction.

The acrosome reaction (AR) is a Ca(2+)-dependent event required for sperm to fertilize the egg. The activation of T-type voltage-gated Ca(2+) channels plays a key role in the induction of this process. This report describes the actions of two toxins from the scorpion Parabuthus granulatus named kurtoxin-like I and II (KLI and KLII, respectively) on sperm Ca(2+) channels. Both toxins decrease T-type Ca(2+) channel activity in mouse spermatogenic cells and inhibit the AR in mature sperm. Saturating concentrations of the toxins inhibited at most approximately 70% of the whole-cell Ca(2+) current, suggesting the presence of a toxin-resistant component. In addition, both toxins inhibited approximately 60% of the AR, which is consistent with the participation of T-type Ca(2+) channels in the sperm AR.

Acrosome Reaction↗
PubMed1983

Photoaffinity labeling of alpha- and beta- scorpion toxin receptors associated with rat brain sodium channel.

Azido nitrophenylaminoacetyl [125I]iodo derivative of toxin II from Centruroides suffusus suffusus, a beta-toxin, and azido nitrophenylaminoacetyl [125I]iodo derivative of toxin V from Leiurus quinquestriatus quinquestriatus, an alpha-toxin, have been covalently linked after binding to their receptor sites that are related to the voltage sensitive sodium channel present in rat brain synaptosomes. Both derivatives labeled two polypeptides of 253000 +/- 20000 and 35000 +/- 2000 mol. wt. Labeling was blocked for each derivative by a large excess of the corresponding native toxin but no cross inhibition was obtained. These results suggest that both alpha - and beta - scorpion toxin receptors are located on or near the same two membrane polypeptides which may be part of the voltage dependent sodium channel.

Affinity Labels↗
PubMed1990

Tryptophan-47 rotational isomerization in variant-3 scorpion neurotoxin. A combination thermodynamic perturbation and umbrella sampling study.

A combination thermodynamic perturbation and umbrella sampling study predicts two free energy wells for the rotational isomerization of the variant-3 scorpion neurotoxin tryptophan-47 indole side chain. One well has the indole side chain in the crystallographic orientation; the other has the indole rotated approximately 220 degrees to form a new conformation with a relative free energy of 3 +/- 2 kcal/mol. The activation barrier is 8.5 kcal/mol from the crystallographic well, from which transition state theory predicts a rate of escape of 2 x 10(5) s-1. Correlations in the displacements of side chains neighboring tryptophan-47 and the isomerization reaction coordinate last up to 20 ps. Favorable conditions of experimental verification are discussed.

Algorithms↗