Hanatoxin

Hanatoxin
SCOP classification[1]
Class Small proteins
Fold Knottins (small inhibitors, toxins, lectins)
Superfamily omega toxin-like
Family Spider toxins
Protein Hanatoxin (HaTx, HaTx1, HaTx2, κ-TRTX-Gr1a)

Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula (Swartz & MacKinnon 1995). The toxin is primarily known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold (Swartz & MacKinnon 1997).

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 is the founding member of a family of spider toxins which inhibit voltage-gated potassium channels by modifying the voltage-sensor (Swartz & MacKinnon 1995,Takahashi 2000). 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 (Lee 2004).

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 (Li-Smerin & Swartz 1998). Hanatoxin binds to the S3-S4 link of K+ channel-subunits, specifically the S3b segment (Gonzalez 2000, Li-Smerin & Swartz 2001), and may bind to multiple subunits in a single ion channel (Swartz & MacKinnon 1997).

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 (Huang, Shiau & Lou 2007).

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.[2] 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 min (Escoubas & Rash 2004).

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 (Tintinalli 2004).

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 (Escoubas & Bosmans 2007). One of the most promising therapeutic uses of hanatoxin is treatment of type-2 diabetes, by helping the regulation of insulin secretion (Herrington 2006). While HaTx1 has successfully been synthesized by fusion in E. coli bacteria, its yield is very low (~1%), limiting its pharmacological use (Lee 2004).

References

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. 

Escoubas, P.; Bosmans, F. (2007). "Spider peptide toxins as leads for drug development". Natural product reports: 1–13. 

Gonzalez, C. e.a. (2000). "Modulation of the Shaker K(+) channel gating kinetics by the S3-S4 linker.". Journal of General Physiology. 115: 193–208. doi:10.1085/jgp.115.2.193. 

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. 

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. 

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. 

Li-Smerin, Y.; Swartz, K.J. (1998). "Gating modifier toxins reveal a conserved structural motif in voltage-gated Ca2+ and K+ channels". Biophysics. 95: 8585–8589. doi:10.1073/pnas.95.15.8585. 

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: 205–218. doi:10.1085/jgp.117.3.205. 

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. 

Swartz, K.J.; MacKinnon, R. (1997). "Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites". Neuron. 18: 665–673. doi:10.1016/s0896-6273(00)80306-2. 

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. 

Tintinalli, J. e.a. (2004). Tintinalli’s Emergency Medicine: A comprehensive Study Guide, 7e. New York, NY McGraw-Hill, Chapter 50, 205.

Notes

  1. ↑ http://supfam.org/SUPERFAMILY/cgi-bin/search.cgi?search_field=hanatoxin, consulted 10th Oct. 2012.
  2. ↑ http://www.t3db.org/toxins, consulted 9th Oct. 2012.
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