Hanatoxin

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Hanatoxin
SCOP classification [1]
ClassSmall proteins
FoldKnottins (small inhibitors, toxins, lectins)
Superfamilyomega toxin-like
Family Spider toxins
ProteinHanatoxin (HaTx, HaTx1, HaTx2, κ-TRTX-Gr1a)

Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. [2] 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. [3]

Contents

Sources

Hanatoxin is a spider toxin from the venom of Grammostola spatulata.

Chemistry

Hanatoxin is the common name for two 4.1 kDa protein toxins, HaTx1 and HaTx2, which are similar in structure. HaTx is a peptide consisting of the following 35 amino-acids:

Glu-Cys-Arg-Tyr-Leu-Phe-Gly-Gly-Cys-Lys-Thr-Thr-***-Asp-Cys-Cys-Lys-His-Leu-Gly-Cys-Lys-Phe-Arg-Asp-Lys-Tyr-Cys-Ala-Trp-Asp-Phe-Thr-Phe-Ser

where *** is Ser for HaTx1 and Ala for HaTx2. First discovered in 1995, the difference in amino-acids and structure compared to other toxins known at that time has made hanatoxin the founding member of a family of spider toxins which inhibit voltage-gated potassium channels by modifying the voltage-sensor. [2] [4] Its amino-acid sequence is homologous to various other toxins, including SGTx1 (76%) and grammotoxin (43%), both of which have similar gating-modification properties as hanatoxin. [5]

Target

Hanatoxin binds to several types of voltage-gated ion channels. While the affinity is the highest for the Kv2.1 and Kv4.2 channels, it has been shown that the toxin may also bind to α1A voltage-gated Ca2+ channels. [6] Hanatoxin binds to the S3-S4 link of K+ channel-subunits, specifically the S3b segment, [7] [8] and may bind to multiple subunits in a single ion channel. [3]

Mode of action

Similar to α-scorpion toxins, Hanatoxin inhibits – but does not block – the activation of, primarily, voltage-gated potassium channels. The S3-S4 link, where hanatoxin binds, is important for voltage-sensing and gate activation. By binding to the S3b segment, the S3b segment is pushed to the N-terminus of the S4 segment, restricting movement and, therefore, requiring a higher depolarization for channel-activation. [9]

Toxicity

While the effects of hanatoxin on its own are not thoroughly studied, it is part of the venom of Grammostola spatulata, which is considered slightly venomous to humans. The tarantula venom causes localized pain, itching and burning and does not seem to have any long-term effects on humans. [10] However, it is possible to have an allergic reaction to the venom, which could cause anaphylaxis, breathing problems and chest pains. The venom is lethal to smaller animals like mice: 0.1 ml of the venom is lethal to mice within about 5 minutes. [11]

Treatment

The bite of Grammostola spatulata should be treated as a regular puncture wound. Washing and cleaning of the area is required and, if the reaction to the poison is too extreme, hospitalization and / or specialized medication may be required. Recovery from the bite usually takes about a week. [12]

Therapeutic use

Due to its specificity for particular ion-channels, hanatoxin has been recognized as a candidate for therapeutic drug development. The potassium channels that hanatoxin inhibits have huge diversity and are involved in a number of functions such as regulation of heart rate, insulin injection and muscle contraction. [13] One of the most promising therapeutic uses of hanatoxin is treatment of type-2 diabetes, by helping the regulation of insulin secretion. [14] While HaTx1 has successfully been synthesized by fusion in E. coli bacteria, its yield is very low (~1%), limiting its pharmacological use. [5]

Related Research Articles

omega-Grammotoxin SIA (ω-grammotoxin SIA) is a protein toxin that inhibits P, Q, and N voltage-gated calcium channels (Ca2+ channels) in neurons.

Margatoxin

Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of Centruroides margaritatus, also known as the Central American Bark Scorpion. Margatoxin was first discovered in 1993. It was purified from scorpion venom and its amino acid sequence was determined.

Agitoxin

Agitoxin is a toxin found in the venom of the scorpion Leiurus quinquestriatus hebraeus. Other toxins found in this species include charybdotoxin (CTX). CTX is a close homologue of Agitoxin.

Grammotoxin

Grammotoxin is a toxin in the venom of the tarantula Grammostola spatulata. It is a protein toxin that inhibits P-, Q- and N-type voltage-gated calcium channels in neurons. Grammotoxin is also known as omega-grammotoxin SIA.

Heteropodatoxin

Heteropodatoxins are peptide toxins from the venom of the giant crab spider Heteropoda venatoria, which block Kv4.2 voltage-gated potassium channels.

Spider toxin Family of toxins produced by spiders

Spider toxins are a family of proteins produced by spiders which function as neurotoxins. The mechanism of many spider toxins is through blockage of calcium channels.

BeKm-1 is a toxin from the Central Asian scorpion Buthus eupeus. BeKm-1 acts by selectively inhibiting the human Ether-à-go-go Related Gene (hERG) channels, which are voltage gated potassium ion channels.

Jingzhaotoxin proteins are part of a venom secreted by Chilobrachys jingzhao, the Chinese tarantula. and act as neurotoxins. There are several subtypes of jingzhaotoxin, which differ in terms of channel selectivity and modification characteristics. All subspecies act as gating modifiers of sodium channels and/or, to a lesser extent, potassium channels.

Heteroscodratoxin-1

Heteroscodratoxin-1 is a neurotoxin produced by the venom glands of Heteroscodra maculata that shifts the activation threshold of voltage-gated potassium channels and the inactivation of Nav1.1 sodium channels to more positive potentials.

Vanillotoxin Chemical compound

Vanillotoxins are neurotoxins found in the venom of the tarantula Psalmopoeus cambridgei. They act as agonists for the transient receptor potential cation channel subfamily V member 1 (TRPV1), activating the pain sensory system. VaTx1 and 2 also act as antagonists for the Kv2-type voltage-gated potassium channel (Kv2), inducing paralytic behavior in small animals.

Guangxitoxin

Guangxitoxin, also known as GxTX, is a peptide toxin found in the venom of the tarantula Plesiophrictus guangxiensis. It primarily inhibits outward voltage-gated Kv2.1 potassium channel currents, which are prominently expressed in pancreatic β-cells, thus increasing insulin secretion.

Theraphosa leblondi toxin (TLTx) is a toxin occurring in three different forms (subtypes) that are purified and sequenced from the venom of the giant tarantula Theraphosa blondi. This toxin selectively inhibits Kv4.2 voltage-gated potassium channels by acting as a gating modifier.

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.

Spinoxin is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.

HgeTx1 (systematic name: α-KTx 6.14) is a toxin produced by the Mexican scorpion Hoffmanihadrurus gertschi that is a reversible blocker of the Shaker B K+-channel, a type of voltage-gated potassium channels.

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.

LmαTX5 is an α-scorpion toxin which inhibits the fast inactivation of voltage-gated sodium channels. It has been identified through transcriptome analysis of the venom gland of Lychas mucronatus, also known as the Chinese swimming scorpion – a scorpion species which is widely distributed in Southeast Asia.

GiTx1

GiTx1 (β/κ-theraphotoxin-Gi1a) is a peptide toxin present in the venom of Grammostola iheringi. It reduces both inward and outward currents by blocking voltage-gated sodium and potassium channels, respectively.

BscTx3

BcsTx3, also known as Kappa-actitoxin-Bsc4a, is a neurotoxin that blocks voltage-gated potassium channel (Kv1/KCNA). It is purified from the venom of Bunodosoma caissarum.

Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels., voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation

References

  1. ↑ http://supfam.org/SUPERFAMILY/cgi-bin/search.cgi?search_field=hanatoxin, consulted 10th Oct. 2012.
  2. 1 2 Swartz, K.J.; MacKinnon, R. (1995). "An Inhibitor of the Kv2.1 Potassium Channel Isolated from the Venom of a Chilean Tarantula". Neuron. 15 (4): 941–949. doi: 10.1016/0896-6273(95)90184-1 . PMID   7576642. S2CID   11188679.
  3. 1 2 Swartz, K.J.; MacKinnon, R. (1997). "Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites". Neuron. 18 (4): 665–673. doi: 10.1016/s0896-6273(00)80306-2 . PMID   9136774. S2CID   17929074.
  4. ↑ Takahashi, H. e.a. (2000). "Solution structure of hanatoxin1, a gating modifier of voltage-dependent K+ channels: common surface features of gating modifier toxins". Journal of Molecular Biology. 297 (3): 771–780. doi:10.1006/jmbi.2000.3609. PMID   10731427.
  5. 1 2 Lee, C. e.a. (2004). "Solution Structure and Functional Characterization of SGTx1, a Modifier of Kv2.1 Channel Gating". Biochemistry. 43 (4): 890–897. doi:10.1021/bi0353373. PMID   14744131.
  6. ↑ Li-Smerin, Y.; Swartz, K.J. (1998). "Gating modifier toxins reveal a conserved structural motif in voltage-gated Ca2+ and K+ channels". Proceedings of the National Academy of Sciences. 95 (15): 8585–8589. Bibcode:1998PNAS...95.8585L. doi: 10.1073/pnas.95.15.8585 . PMC   21119 . PMID   9671721.
  7. ↑ Gonzalez, C. e.a. (2000). "Modulation of the Shaker K(+) channel gating kinetics by the S3-S4 linker". Journal of General Physiology. 115 (2): 193–208. doi:10.1085/jgp.115.2.193. PMC   2217197 . PMID   10653896.
  8. ↑ Li-Smerin, Y.; Swartz, K.J. (2001). "Helical structure of the COOH terminus of S3 and its contribution to the gating modifier toxin receptor in voltage-gated ion channels". Journal of General Physiology. 117 (3): 205–218. doi:10.1085/jgp.117.3.205. PMC   2225613 . PMID   11222625.
  9. ↑ Huang, P.; Shiau, Y.; Lou, K. (2007). "The interaction of spider gating modifier peptides with voltage-gated potassium channels". Toxicon. 49 (2): 285–292. doi:10.1016/j.toxicon.2006.09.015. PMID   17113615.
  10. ↑ http://www.t3db.org/toxins, consulted 9th Oct. 2012.
  11. ↑ Escoubas, P.; Rash, L. (2004). "Review Tarantulas: eight-legged pharmacists and combinatorial chemists". Toxicon. 43 (5): 555–574. doi:10.1016/j.toxicon.2004.02.007. PMID   15066413.
  12. ↑ Tintinalli, J. e.a. (2004). Tintinalli’s Emergency Medicine: A comprehensive Study Guide, 7e. New York, NY McGraw-Hill, Chapter 50, 205.
  13. ↑ Escoubas, P.; Bosmans, F. (2007). "Spider peptide toxins as leads for drug development". Natural Product Reports. 2 (6): 1–13. doi:10.1517/17460441.2.6.823. PMID   23489000. S2CID   22614679.
  14. ↑ Herrington, J. e.a. (2006). "Blockers of the Delayed-Rectifier Potassium Current in Pancreatic β-Cells Enhance Glucose-Dependent Insulin Secretion". Diabetes. 55 (4): 1034–1042. doi: 10.2337/diabetes.55.04.06.db05-0788 . PMID   16567526.
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