Huwentoxin
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Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena.[1] While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.
Huwentoxins are neurotoxic peptides produced by the Chinese bird spider, Haplopelma schmidti.[2]
Overview
The venom of H. schmidti contains a large variety of neurotoxins, which function to paralyze the spider's prey. So far, 14 of the isolated primarily neurotoxic peptide components have been characterized and investigated. In the following, two subfamilies of the HWTX are described: those targeting voltage-gated calcium channels, and those targeting voltage-gated sodium channels.
Toxins targeting voltage-gated calcium channels (VGCC)
Huwentoxin-I
HWTX-I is the most abundant toxic component in the venom of H. schmidti. It inhibits presynaptic N-type Ca2+ channels.
Chemistry
The molecular weight of HWTX-I is 3750 Da. The toxin comprises 33 residues, including six cysteines that form three disulfide linkages.[3][4] These were assigned as Cys2-Cys17, Cys9-Cys22, and Cys16-Cys29 and are buried within the molecule.[5] The molecule adopts a compact structure consisting of a small triple-stranded antiparallel beta-sheet and five beta-turns. It was found that the structure contains an inhibitor cystine knot (ICK) motif. To form this motif, three disulfide bridges are needed. Two of them create a loop through which the third disulfide bridge passes.[4][6][7] The structure of HWTX-I is very stable, secondary structure elements do not significantly alter under different pH conditions or after heating.[8]
Mode of action
HWTX-I selectively inhibits N-type HVA channels.[9] A recent study found that HWTX-I also inhibits Na+ channels.[10]
Effects
In mice the intraperitoneal LD50 of HWTX-I is 0.70 mg/kg, the intracisternal LD50 has been determined as 9.40 μg/kg. Neurotoxic symptoms after intraperitoneal injection were gasping, excitation, spastic paralysis of the hindlimb and asynergia.[3][11]
HWTX-I is a potential novel analgesic pharmaceutic.[12] Epidural administration of HWTX-I in rats with chronic neuropathic pain blocked heat hyperalgesia and mechanical allodynia in the injured hindpaw of rats, indicating that epidurally administered HWTX-I could alleviate neuropathic pain.[13] Cytosolic Ca2+ overload is one of the primary factors for inflammatory cells activation, therefore Ca2+ channel blockers can have a potential role as an anti-inflammatory drug. HWTX-I can relieve pain in the inflammatory joints and eliminate arthrocele to some degree. In a rat model of rheumatoid arthritis HWTX-I is able to decrease the concentration of tumor necrosis factor α (TNF-α) in serum and decrease the mRNA expression level interleukin 1β (IL-1β) and interleukin 6 (IL-6).[14]
Huwentoxin-X
HWTX-X is the smallest peptide among the huwentoxins so far isolated.
Chemistry
HWTX-X has a molecular mass of 2931 Da. It comprises 28 amino acid residues, including six cysteine residues forming three disulfide bridges. Like most huwentoxins, it adopts the ICK motif.[15] HWTX-X shows little homology with other huwentoxins, however, it can cause reversible blockage of N-type Ca2+ channels in rat dorsal root ganglion cells under whole-cell voltage clamp conditions. It does show more than 50% homology with the toxin Ptu1 from the assassin bug Peirates turpis and ω-conotoxin SVIA from the Conus striatus, two N-type Ca2+ blockers.[16]
Mode of action
HWTX-X has selectivity for isoforms of N-type Ca2+ channels, compared with ω-conotoxins GVIA and MVIIA.
Effects
HWTX-X specifically blocks GVIA-sensitive, N-type Ca2+ channels in rat dorsal root ganglion cells. It does not block L-type Ca2+ channels. While structurally similar to ω-conotoxins that block the twitch response to electrical nerve stimulation, HWTX-X has no effect on the twitch response of rat vas deferens.[15]
