Tityustoxin

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Tityustoxin is a toxin found in the venom of scorpions from the subfamily Tityinae. By binding to voltage-dependent sodium ion channels and potassium channels, they cause sialorrhea, lacrimation and rhinorrhea.

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Scorpions are distributed among six families. Only those of the family Buthidae are dangerous to humans. Within this family, the subfamily Tityinae cause the most scorpion poisoning in humans. [1] These species are found in Brazil ( Tityus serrulatus, T. bahiensis and T. stigmurus ) and in Northern and Southern Venezuela ( T. discrepans ). [2] The venom of Tityus serrulatus is the most potent of these. [1]

Chemistry

The crude venom of T. serrulatus contains different toxins. Some of the strongest derivates are the neurotoxins tityustoxin and toxin Ts-g. [3] Two types of toxins are considered to be responsible for the main toxic effect: toxin gamma (a β-type toxin) and tityustoxin (TsTX, an α-type toxin), both with a specific affinity to the sodium channel. [4] Other types of venom are: TsTX-kα, a 37 amino acid, [5] toxin gamma (TsTX-γ and TsTX-I) with 61 amino acid residues is the major neurotoxin of this venom. TsTX-Kβ has a longer chain. [2] K+ channels blocking peptides are single chain polypeptides of 30-40 amino acids with three disulphide bridges. [6] The toxin with four disulphide bonds is from TsTX-IV. This contains 41 amino acid residues. [2]

Targets

Mode of action

Two types of toxin are interesting: α-Scorpion toxins bind at site 3 of Na1 channels, causing a slowing of their inactivation. β-Scorpion toxins bind at site 4, shifting the activation of Na1 currents (INa) toward more negative potentials. [7] Tityustoxin causes cell depolarization, activating Na+ channels and increasing the Na+ uptake that can affect Ca2+ uptake and can increase acetylcholine (ACh) release from cerebral cortical slices. [8]

Na+ channels

The α-toxins bind to the subunit 3 of the sodium channel, slowing the inactivation and increasing peak current without changing time to peak. [4] This causes cell depolarization that opens calcium channels allowing the influx of Ca2+, triggering ACh release. [8] Both the steady-state activation and inactivation curves are shifted to more negative potentials. [4]

K+ channels

TsTX-I, Ts1 or toxin gamma is a β-type toxin that binds to receptor site 4 and shift the voltage dependence of the sodium channel activation to more negative potentials. [9] TsTX-Ka selectively blocks voltage-gated noninactivating (possibly delayed rectifier) K+ channels in synaptosomes. [10]

Toxicity

The venom of Tityus serrulatus is the most potent of the toxins from the species. [3] Tityustoxin-1, TsTX-I is the most toxic protein among the neurotoxins in this venom, with an intravenous and intracisternal LD50 (mouse) of 76 ± 9 and 1.1 ± 0.3 µg/kg, respectively. The identification of TsTX-I as a potent component of T. serrulatus venom characterized it as the major and main neurotoxin from this venom. [1] Poisoning effects in man evoked by T. serrulatus venom are sialorrhea, lacrimation and rhinorrhea [3] and acute pancreatitis. [1] Catecholamines by the adrenal glands and postganglionic nerve terminals and Ach by ganglions and postganglionic nerve terminals are released when the poison strikes. Also other neurotransmitters are released by the whole venom and isolated toxins. [1] In rats, the Tityustoxin caused dramatic effects on the circulatory and respiratory systems, consisting of hypotension, tachypnea, hyperpnea, ataxic and gasping breathing. Following these initial effects, 5 or 10 µg of TsTX induced hypertension and hyperpnea. The largest dose produced apnea and death about 70 min later. [11]

Treatment

The lung edema induced by TsTX is blocked by phenobarbital. [12] Rabbit anti-TsNTxP antibodies displayed cross-reactivity with the scorpion toxins and showed in vitro neutralizing capacity. Thus, this protein emerges as a strong candidate for the production of antiserum to be used in the treatment of scorpion stings. The nontoxic recombinant protein can induce a level of circulating antibodies sufficient to neutralize the toxic effects of Tityus toxins and is a good candidate for use in the production of a new generation of neutralizing polyclonal antibodies for clinical use. [13]

Related Research Articles

<i>Tityus</i> (genus) Genus of scorpions

Tityus is a large genus of thick-tailed scorpions, the namesake of its subfamily Tityinae. As of 2021, Tityus contains more than 220 described species distributed in Central America and South America, from Costa Rica to Argentina. Species in the genus Tityus have been studied for hundreds of years, long before the taxonomic classification was put in place. Tityus tend to be of medium size for scorpions, roughly 50 to 70 millimeters long. They are dark brown or red in color, and can exhibit sexual dimorphism. They can live in a variety of environments, ranging from urban to arid mountains to the Amazon Rainforest. Tityus scorpions are best known for their venom and potent sting. The genus contains several dangerously venomous scorpions, the best known of which is the Brazilian yellow scorpion, T. serrulatus. Its venom can cause severe illness, and in the young, old and infirm even death. Some experts have argued that the genus as a whole may be paraphyletic, which could explain the knowledge gaps related to Tityus. 

Phoneutria nigriventer toxin-3 is more commonly referred to as PhTx3.

Birtoxin is a neurotoxin from the venom of the South African Spitting scorpion. By changing sodium channel activation, the toxin promotes spontaneous and repetitive firing much like pyrethroid insecticides do

Bestoxin is a neurotoxin from the venom of the South African spitting scorpion Parabuthus transvaalicus. Most likely, it targets sodium channel function, thus promoting spontaneous and repetitive neuronal firing. Following injection into mice, it causes non-lethal writhing behaviour.

BmKAEP is a neurotoxin from the venom of the Manchurian scorpion (Mesobuthus martensii). It is a β-toxin, which shift the activation voltage of sodium channels towards more negative potentials.

<i>Tityus serrulatus</i> Species of scorpion

Tityus serrulatus, the Brazilian yellow scorpion, is a species of scorpion of the family Buthidae. It is native to Brazil, and its venom is extremely toxic. It is the most dangerous scorpion in South America and is responsible for the most fatal cases.

Ikitoxin is a neurotoxin from the venom of the South African Spitting scorpion that targets voltage-sensitive sodium channels. It causes unprovoked jumps in mice following intracerebroventricular injections.

Butantoxin (BuTX) is a compound of the venom of three Brazilian and an Argentinean scorpion species of the genus Tityus. Butantoxin reversibly blocks the voltage-gated K+ channels Shaker B and Kv1.2, and the Ca2+-activated K+ channelsKCa 1.1 and KCa 3.1.

BotIT2 is a neurotoxin from the scorpion Buthus occitanus tunetanus, which modifies activation and slows down the deactivation of voltage gated sodium channels.

<span class="mw-page-title-main">Bactridines</span>

Bactridines are a group of six antibacterial peptides from the venom of the Tityusdiscrepans scorpion. They exclusively target sodium channels. Bactridines are unique in that this scorpion toxin acts on sodium channels of both bacteria and eukaryotes.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

TsIV is a toxin from the venom of the Brazilian scorpion Tityus serrulatus which slows the inactivation of sodium channels.

<span class="mw-page-title-main">Cll1</span> Scorpion protein

Toxin Cll1 is a toxin from the venom of the Mexican scorpion Centruroides limpidus limpidus, which changes the activation threshold of sodium channels by binding to neurotoxin binding site 4, resulting in increased excitability.

Ts15 is produced by the Brazilian yellow scorpion Tityus serrulatus. It targets voltage-gated potassium channels, primarily the subtypes Kv1.2 and Kv1.3.

Tityustoxin peptide 2 (TsPep2) is a peptide isolated from the venom of the Tityus serrulatus. It belongs to a class of short peptides, together with Tityustoxin peptide 1 and Tityustoxin peptide 3.

<span class="mw-page-title-main">Noxiustoxin</span>

Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion Centruroides noxius Hoffmann which block voltage-dependent potassium channels and calcium-activated potassium channels.

Beta-mammal toxin Cn2, also known as Cn2 toxin, is a single chain β-scorpion neurotoxic peptide and the primary toxin in the venom of the Centruroides noxius Hoffmann scorpion. The toxin specifically targets mammalian Nav1.6 voltage-gated sodium channels (VGSC).

<span class="mw-page-title-main">Tst26</span>

The Tst26 toxin is a voltage-gated potassium channel blocker present in the venom of Tityus stigmurus, a species of Brazilian scorpion. Tst26 selectively blocks Kv1.2 and Kv1.3 channels.

U7-ctenitoxin-Pn1a (or U7-CNTX-Pn1a for short) is a neurotoxin that blocks TRPV1 channels, and can exhibit analgestic effects. It is naturally found in the venom of Phoneutria nigriventer.

Ts8 TsK2; Tityustoxin K-beta; TsTX-K beta and TsTx-Kβ) is a neurotoxin present in the venom of the Brazilian yellow scorpion, Tityus serrulatus. Ts8 targets voltage-gated potassium channels, by selective inhibition of the Kv4.2 channels.

References

  1. 1 2 3 4 5 Corrêa, M.M.; Sampaio, S.V.; Lopes, R.A.; Mancuso, L.C.; Cunha, O.A.B.; Franco, J.J.; Giglio, J.R. (1997). "Biochemical and histopathological alterations induced in rats by Tityus serrulatus scorpion venom and its major neurotoxin tityustoxin-I". Toxicon. 35 (7): 1053–1067. doi:10.1016/s0041-0101(96)00219-x. PMID   9248004.
  2. 1 2 3 4 5 Novello, José C; Arantes, Eliane C; Varanda, Wamberto A; Oliveira, Benedito; Giglio, José R; Marangoni, Sérgio (1999). "TsTX-IV, a short chain four-disulfide-bridged neurotoxin from Tityus serrulatus venom which acts on Ca2+-activated K+ channels". Toxicon. 37 (4): 651–660. doi:10.1016/s0041-0101(98)00206-2. PMID   10082164.
  3. 1 2 3 Clemente, G.T; Rossoni, R.B; Safe, J.M.M; Freire-Maia, L (1999). "Effects of crude venom, tityustoxin and toxin Ts-γ from Tityus serrulatus scorpion on secretion and structure of the rat submandibular gland". Archives of Oral Biology. 44 (2): 103–110. doi:10.1016/s0003-9969(98)00109-5. PMID   10206328.
  4. 1 2 3 Mesquita, Michel B.S; Moraes-Santos, Tasso; Moraes, M.árcio F.D (2003). "Centrally injected tityustoxin produces the systemic manifestations observed in severe scorpion poisoning". Toxicology and Applied Pharmacology. 187 (1): 58–66. doi:10.1016/s0041-008x(02)00036-4. PMID   12628585.
  5. ↑ Werkman, T. R.; Gustafson, T. A.; Rogowski, R. S.; Blaustein, M. P.; Rogawski, M. A. (August 1993). "Tityustoxin-K alpha, a structurally novel and highly potent K+ channel peptide toxin, interacts with the alpha-dendrotoxin binding site on the cloned Kv1.2 K+ channel". Molecular Pharmacology. 44 (2): 430–436. ISSN   0026-895X. PMID   8355670.
  6. ↑ Legros, Christian; Oughuideni, Razika; Darbon, Hervé; Rochat, Hervé; Bougis, Pierre E.; Martin-Eauclaire, Marie-France (1996-07-15). "Characterization of a new peptide from Tityus serrulatus scorpion venom which is a ligand of the apamin-binding site". FEBS Letters. 390 (1): 81–84. doi: 10.1016/0014-5793(96)00616-3 . ISSN   1873-3468. PMID   8706835.
  7. ↑ Conceicao, I. M.; Lebrun, I.; Cano-Abad, M.; Gandia, L.; Hernandez-Guijo, J. M.; Lopez, M. G.; Villarroya, M.; Jurkiewicz, A.; Garcia, A. G. (1998). "Synergism between toxin-gamma from Brazilian scorpion Tityus serrulatus and veratridine in chromaffin cells". The American Journal of Physiology. 274 (6 Pt 1): C1745–1754. doi:10.1152/ajpcell.1998.274.6.C1745. ISSN   0002-9513. PMID   9611141.
  8. 1 2 Casali, T.A.A.; Gomez, R.S.; Moraes-santos, T.; Gomez, M.V. (1995). "Differential effects of calcium channel antagonists on tityustoxin and ouabain-induced release of [3H]acetylcholine from brain cortical slices". Neuropharmacology. 34 (6): 599–603. doi:10.1016/0028-3908(95)00019-3. PMID   7566495. S2CID   29615707.
  9. ↑ Pessini, Andréa C; Takao, Tânia T; Cavalheiro, Elisângela C; Vichnewski, Walter; Sampaio, Suely V; Giglio, José R; Arantes, Eliane C (2001). "A hyaluronidase from Tityus serrulatus scorpion venom: isolation, characterization and inhibition by flavonoids". Toxicon. 39 (10): 1495–1504. doi:10.1016/s0041-0101(01)00122-2. PMID   11478957.
  10. ↑ Rogowski, R. S.; Krueger, B. K.; Collins, J. H.; Blaustein, M. P. (1994-02-15). "Tityustoxin K alpha blocks voltage-gated noninactivating K+ channels and unblocks inactivating K+ channels blocked by alpha-dendrotoxin in synaptosomes". Proceedings of the National Academy of Sciences. 91 (4): 1475–1479. Bibcode:1994PNAS...91.1475R. doi: 10.1073/pnas.91.4.1475 . ISSN   0027-8424. PMC   43182 . PMID   7509073.
  11. ↑ Lima, E.G.; Freire-Maia, L. (1977). "Cardiovascular and respiratory effects induced by intracerebroventricular injection of scorpion toxin (tityustoxin) in the rat". Toxicon. 15 (3): 225–234. doi:10.1016/0041-0101(77)90048-4. PMID   867438.
  12. ↑ Mesquita, Michel Bernanos Soares; Moraes-Santos, Tasso; Moraes, Márcio Flávio Dutra (2002). "Phenobarbital blocks the lung edema induced by centrally injected tityustoxin in adult Wistar rats". Neuroscience Letters. 332 (2): 119–122. doi:10.1016/s0304-3940(02)00932-1. PMID   12384225. S2CID   8617029.
  13. ↑ Guatimosim, Silvia C.F.; Kalapothakis, Evanguedes; Diniz, Carlos R.; Chávez-Olórtegui, Carlos (2000). "Induction of neutralizing antibodies against Tityus serrulatus toxins by immunization with a recombinant nontoxic protein". Toxicon. 38 (1): 113–121. doi:10.1016/s0041-0101(99)00138-5. PMID   10669016.
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