Hainantoxin

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Hainantoxins (HNTX) are neurotoxins from the venom of the Chinese bird spider Haplopelma hainanum . Hainantoxins specifically inhibit tetrodotoxin-sensitive Voltage-gated sodium channels, thereby causing blockage of neuromuscular transmission and paralysis. [1] [2] Currently, 13 different hainantoxins are known (HNTX-I – HNTX-XIII), but only HNTX-I, -II, -III, -IV and -V have been investigated in detail. [3]

Contents

Sources

HNTX-I, HNTX-III, HNTX-IV and HNTX-V are made by the Chinese bird spider Haplopelma hainanum (=Ornithoctonus hainana, Selenocosmia hainana). [1] [2] [4] [5] [6] [7] [8] [9] [10] [11]

Chemistry

Structure

Hainantoxins I, III, IV and V show high homology, including the presence of three disulfide bonds that form an inhibitor cysteine knot (ICK) motif.

HNTX-I

The main component of the venom of O. hainana is HNTX-I. [12] It has 33 amino acid residues, with a total molecular weight of 3605-3608 Da. HNTX-I contains a short triple-stranded anti-parallel beta-sheet and four beta-turns. [4] The amino acid residues His28 and Asp26 are needed for the bioactivity of HNTX-I. [13]

HNTX-II

HNTX-II has a molecular weight of 4253 Da and contains 37 amino acid residues. The complete amino acid sequence of HNTX-II is NH2-LFECSV SCEIEK EGNKD CKKKK CKGGW KCKFN MCVKV-COOH. [14]

HNTX-III

The structure of HNTX-III consists of 33-35 amino acid residues, which form a beta-sheet with connections between Asp7 and Cys9, Tyr21 and Ser23, and Lys27 and Val30. [6] [8]

HNTX-IV

HNTX-IV has 35 amino acid residues with a total molecular weight of 3989 Da. The first strand consists of an antiparallel beta-sheet. [11] The complete amino acid sequence of HNTX-IV is NH2-ECLGFG KGCNPS NDQCCK SSNLVC SRKHRW CKYEI-CONH2. [11] Lys 27, His28, Arg29 and Lys 32 are the neuroactive amino acid residues. [1] [5] [10]

HNTX-V

HNTX-V consists of 35 amino acid residues. [2] The whole amino acid residue sequence of HNTX-V is NH2-ECLGFG KGCNPS NDQCCK SANLVC SRKHRW CKYEI-COOH. At the active binding site of HNTX-V, Lys27 and Arg 29 are the most important. [2]

Target

Channel

Hainantoxins selectively inhibit tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (VGSCs). [1] [5] [6] [9] Voltage-gated Ca2+ channels (VGCCs), tetrodotoxin-resistant (TTX-R) VGSCs and rectifier-delayed potassium channels are not affected. [8] HNTX-III and HNTX-IV are part of the Huwentoxin-I family. [3] [8] Toxins from the Huwentoxin-I family are thought to bind to site 1 on the sodium channels. Other hainantoxins bind at site 3 of the sodium channels. HNTX-I specifically blocks mammalian Nav1.2 and insect para/tipE channels expressed in Xenopus laevis oocytes. HNTX-I is a weak antagonist of the vertebrate TTX-S VGSCs, but is more potent on insect VGSCs. [4] [10]

Affinity

For the blockage of sodium channels, electrostatic interactions or hydrogen bonds are needed. Important for the electrostatic interaction is the presence of a positively charged region in the toxin, because the receptor site of the sodium channel contains a lot of negatively charged residues. [1] [2] In HNTX-I, the positively charged residues and a vicinal hydrophobic patch have most influence on the binding to the sodium channels. [4] HNTX-IV has a positively charged patch containing the amino acids Arg26, Lys27, His28, Arg29 and Lys32, of which Lys27, Arg29 and Lys32 are the most important for interaction with the TTX-S VGSCs. [10] [15] HNTX-V also shows an interface of positively charged amino acids that are responsible for the binding with the TTX-S VGSCs, where also Lys27 and Arg29 are the most important. Subtle differences in the positively charged patch can result in altered electrostatic properties, causing altered pharmacological effects. [4]

Table 1: IC50 values of four subgroups of hainantoxins

IC50
HNTX-I68 μM [4]
HNTX-III1.1 nM [8]
HNTX-IV44.6 nM [8]
HNTX-V42.3 nM [2]

Mode of action

HNTX-I, HNTX-III, HNTX-IV, and HNTX-V are thought to bind to site 1 of voltage-dependent sodium channels, similar to TTX, and thereby block the channel pore. They do not alter activation and inactivation kinetics. [1] [4] Ion selectivity of the VGSCs is not changed by hainantoxin. [8] [9] The mode of action of HNTX-II is unclear, but is unlikely to involve sodium channels. [14]

Toxicity

Symptoms

Hainantoxins can affect both vertebrates and invertebrates. HNTX-I has no significant effect on insects or rats. [2] [12] HNTX-III and HNTX-IV cause spontaneous contractions of the diaphragm muscle and the vas deferens smooth muscle of the rat. [8] [9] HNTX-III and HNTX-IV are able to paralyze cockroaches, and HNTX-IV can even paralyze rats. [15]

LD50

Intracerebroventricular injection in mice with HNTX-II shows a LD50 of 1.41 μg/g. The intraperitoneal LD50 value of HNTX-IV in mice is 0.2 mg/kg. [8] [9] HNTX-III is 40 times more potent that HNTX-IV. [8]

Therapeutic use

HNTX-III and HNTX-IV have an antagonistic effect on the toxin BMK-I, a toxic protein in the venom of the scorpion Buthus martensii. [8]

Related Research Articles

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Dendrotoxin

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Cyriopagopus hainanus is a species of spider in the family Theraphosidae (tarantulas), found in China. It is one of a number of species from China and Vietnam known as "Chinese bird spider". It produces a venom containing numerous compounds capable of blocking neurotransmitters, including neurotoxic peptides called hainantoxins.

Delta atracotoxin

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Agitoxin

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Scorpion toxin

Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, voltage-gated sodium channels, voltage-gated potassium channels, and Transient Receptor Potential (TRP) channels. The result of this action is to activate or inhibit the action of these channels in the nervous and cardiac organ systems. For instance, α-scorpion toxins MeuNaTxα-12 and MeuNaTxα-13 from Mesobuthus eupeus are neurotoxins that target voltage-gated Na+ channels (Navs), inhibiting fast inactivation. In vivo assays of MeuNaTxα-12 and MeuNaTxα-13 effects on mammalian and insect Navs show differential potency. These recombinants exhibit their preferential affinity for mammalian and insect Na+ channels at the α-like toxins' active site, site 3, in order to inactivate the cell membrane depolarization faster[6]. The varying sensitivity of different Navs to MeuNaTxα-12 and MeuNaTxα-13 may be dependent on the substitution of a conserved Valine residue for a Phenylalanine residue at position 1630 of the LD4:S3-S4 subunit or due to various changes in residues in the LD4:S5-S6 subunit of the Navs. Ultimately, these actions can serve the purpose of warding off predators by causing pain or to subdue predators.

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<i>delta</i>-Palutoxin

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Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold.

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Pandinus imperator (Pi3) toxin

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LmαTX3 is an α-scorpion toxin from Lychas mucronatus. that inhibits fast inactivation of voltage gated sodium-channels (VGSCs).

GTx1-15 is a toxin from the Chilean tarantula venom that acts as both a voltage-gated calcium channel blocker and a voltage-gated sodium channel blocker.

References

  1. 1 2 3 4 5 6 Li D et al. Structure--activity relationships of hainantoxin-IV and structure determination of active and inactive sodium channel blockers. J Biol Chem. 2004 Sep 3;279(36):37734-40. Epub 2004 Jun 16.
  2. 1 2 3 4 5 6 7 Xiao YC, Liang SP. Purification and characterization of Hainantoxin-V, a tetrodotoxin-sensitive sodium channel inhibitor from the venom of the spider Selenocosmia hainana. Toxicon. 2003 May;41(6):643-50.
  3. 1 2 "Family:%22huwentoxin-1 family%22 in UniProtKB".
  4. 1 2 3 4 5 6 7 Li D, et al. Function and solution structure of hainantoxin-I, a novel insect sodium channel inhibitor from the Chinese bird spider Selenocosmia hainana. FEBS Lett. 2003 Dec 18;555(3):616-22.
  5. 1 2 3 Xu X et al. Solid-phase synthesis and biological characterization of S12A-HNTX-IV and R29A-HNTX-IV: two mutants of hainantoxin-IV. Sheng Wu Gong Cheng Xue Bao. 2005 Jan;21(1):92-6.
  6. 1 2 3 Zeng XZ et al. Sequence-specific assignment of 1H-NMR resonance and determination of the secondary structure of Jingzhaotoxin-I. Acta Biochim Biophys Sin (Shanghai). 2005 Aug;37(8):567-72.
  7. ↑ Honma T et al. Novel peptide toxins from acrorhagi, aggressive organs of the sea anemone Actinia equina. Toxicon. 2005 Dec 1;46(7):768-74. Epub 2005 Sep 23.
  8. 1 2 3 4 5 6 7 8 9 10 11 Xiao Y, Liang S. Inhibition of neuronal tetrodotoxin-sensitive Na+ channels by two spider toxins: hainantoxin-III and hainantoxin-IV. Eur J Pharmacol. 2003 Sep 5;477(1):1-7.
  9. 1 2 3 4 5 Xiao YC, Liang SP. Inhibition of sodium channels in rat dorsal root ganglion neurons by Hainantoxin-IV, a novel spider toxin. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003 Jan;35(1):82-5.
  10. 1 2 3 4 Liu Y et al. A positively charged surface patch is important for hainantoxin-IV binding to voltage-gated sodium channels. J Pept Sci. 2012 Oct;18(10):643-9. doi: 10.1002/psc.2451. Epub 2012 Aug 27.
  11. 1 2 3 XIONG Xia et al. Effects of Arg26 and Lys27 mutation on the bioactivity of HNTX-IV
  12. 1 2 Liu Z et al. Isolation and characterization of hainantoxin-IV, a novel antagonist of tetrodotoxin-sensitive sodium channels from the Chinese bird spider Selenocosmia hainana. Cell Mol Life Sci. 2003 May;60(5):972-8.
  13. ↑ Nicholson GM. Insect-selective spider toxins targeting voltage-gated sodium channels. Toxicon. 2007 Mar 15;49(4):490-512. Epub 2006 Dec 5.
  14. 1 2 Pan J-Y, Yu Z-Q. Isolation and characterization of Hainantoxin-II, a new neurotoxic peptide from the Chinese bird spider (Haplopelma hainanum). Zool. Res. 2010 6:570-4.
  15. 1 2 Wang RL et al. Mechanism of action of two insect toxins huwentoxin-III and hainantoxin-VI on voltage-gated sodium channels. J Zhejiang Univ Sci B. 2010 Jun;11(6):451-7.
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