User:Boukaijm/sandbox/GiTx1 (β/κ-theraphotoxin-Gi1a)
Source code wikipedia:
| GiTx1 (β/κ-theraphotoxin-Gi1a) | |||||||
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 Structural image of GiTx1 | |||||||
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| UniProt | C0HJJ7 | ||||||
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GiTx1 (β/κtheraphotoxin-Gi1a) is a peptide toxin present in the venom of Grammostola iheringi. It reduces both inward and outward flow of current by respectively blocking voltage-gated sodium and potassium channels.
Etymology & Source
[edit]GiTx1 is found in the venom of the Grammostola iheringi , a brazilian tarantula of the family Theraphosidae.[1] GiTx1 is an abbreviation of (G)rammostola (i)heringi (T)o(x)in 1 and its rational nomenclature name is β/κ-theraphotoxin-Gi1a.[2]
Chemistry
[edit]GiTx1 is a positively charged protein that consists of 29 amino acids and has a total molecular weight of 3.585 Da.
Its amino acid sequence is characterized to be as followed:
SCQKWMWTCDQKRPCCEDMVCKLWCKIIK
The protein contains 3 sulfide bridges and 6 cysteine residues. This pattern of disulfide bridges between cysteine amino acids creates a motif called an inhibitory cystine knot found in various other spider toxins. The structure of the toxin is further characterized by two short stranded antiparallel beta sheets and two polypeptide loops. [1]
Proteins with similar sequences to GiTx1 such as PaTx1 and PaTx 2, which are both phrixotoxins, have shown to influence voltage gated potassium channels in cardiac cells.[3] Charged residues of GiTx1 are opposite of a set of hydrophobic amino acids similar to the structure of Prototoxin-II, for which this hydrophobic phase is important for the interaction with the voltage-gated sodium channel sensor domain.[4]
Target and mode of action
[edit]GiTx1 is a promiscuous neurotoxin, as it inhibits multiple voltage-gated ion channel families. It is known that GiTx1 affects voltage gated sodium and potassium channels, the overall current over these channels will be decreased, but the blockage is reversible.
GiTx1 is found to inhibit the current flow through the following channels: mammalian rNav1.2, rNav1.4, mNav1.6, Kv4.3 hERG-potassium channels and arachnid VdNav1, when they are expressed in X. laevis oocytes.
In DRG cells, the overall inhibition is greater for inward sodium current than the outward current of potassium. As the addition of GiTx1 reduces sodium current to 60 percent, and potassium current is reduced to 80 percent.
The effect of GiTx1 is different on the affected channels. The IC50 of hERG -potassium channels is 3695 ± 127 nM while the IC50 of Nav1.6 is 156 ± 150 nM and that of VdNav1 is in the range of between 124 and 13 nM. For Kv4.3 channels, it is known that 90 percent of them are blocked by GiTx1.[1]
Toxicity
[edit]Toxicity in mice
[edit]Using the Grammostola iheringi’s venom by intraperitoneal injection in the range of 0.8-12.8 μg, the venom causes complete paralysation, resulting in death within 30 minutes for higher concentrations. When using the same type of injection with 0.5 μg of GiTx, the toxin shows very low toxicity.
Using the complete venom by injection in the cerebrospinal fluid (i.c.v) the toxicity increases. With a lower concentration (0.1-0.8μg) the mice suffer from multiple symptoms such as rotating movements, disorientation and paralysis. At higher concentrations (0.8-1.6μg) other symptoms occur on top of paralysis with severe mobility difficulty, including grunting and cyanosis. These paralyses are reversible at non-lethal doses. Surviving mice do not show symptoms after a period of 24 hours. Mice which were injected with 1 μg/animal GiTx1 by i.c.v also show this reversible paralysis within the first hour after the injection.[1]
Toxicity in flies
[edit]The Toxicity of the Grammostola iheringi ‘s venom shows a LD50 of 0.20 μg/fly in “Drosophila melanogaster'' while the LD50 of solely GiTx1 is slightly higher, namely 20.9 μg/g. Additionally, the dosage required to induce paralysis differs between GiTx1 and complete venom injection. Using the complete venom mixture, a dosis of 0.015μg/fly is sufficient to induce paralysis, while 0.1-0.4 μg/fly of just GiTx1 is needed for complete paralysation.[1]
References
[edit]- ^ a b c d e Montandon, Gabriela Gontijo; Cassoli, Juliana Silva; Peigneur, Steve; Verano-Braga, Thiago; Santos, Daniel Moreira dos; Paiva, Ana Luiza Bittencourt; Moraes, Éder Ricardo de; Kushmerick, Christopher; Borges, Márcia Helena; Richardson, Michael; Pimenta, Adriano Monteiro de Castro (2020-09-01). "GiTx1(β/κ-theraphotoxin-Gi1a), a novel toxin from the venom of Brazilian tarantula Grammostola iheringi (Mygalomorphae, Theraphosidae): Isolation, structural assessments and activity on voltage-gated ion channels". Biochimie. 176: 138–149. doi:10.1016/j.biochi.2020.07.008. ISSN 0300-9084.
- ^ King, Glenn F.; Gentz, Margaret C.; Escoubas, Pierre; Nicholson, Graham M. (2008-08-01). "A rational nomenclature for naming peptide toxins from spiders and other venomous animals". Toxicon. 52 (2): 264–276. doi:10.1016/j.toxicon.2008.05.020. ISSN 0041-0101.
- ^ Diochot, Sylvie; Drici, Milou-Daniel; Moinier, Danielle; Fink, Michel; Lazdunski, Michel (1999). "Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis". British Journal of Pharmacology. 126 (1): 251–263. doi:10.1038/sj.bjp.0702283. ISSN 1476-5381. PMC 1565788. PMID 10051143.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Henriques, Sónia Troeira; Deplazes, Evelyne; Lawrence, Nicole; Cheneval, Olivier; Chaousis, Stephanie; Inserra, Marco; Thongyoo, Panumart; King, Glenn F.; Mark, Alan E.; Vetter, Irina; Craik, David J. (2016-08-12). "Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7". Journal of Biological Chemistry. 291 (33): 17049–17065. doi:10.1074/jbc.M116.729095. PMC 5016110. PMID 27311819.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)