Hainantoxin

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]

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][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]

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References
  1. 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. 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. https://www.uniprot.org/uniprot/?query=family:%22huwentoxin-1+family%22
  4. 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. 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. 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. 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. 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. 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. XIONG Xia et al. Effects of Arg26 and Lys27 mutation on the bioactivity of HNTX-IV
  12. 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. 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. 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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