Heteroscodratoxin-1

Heteroscodratoxin-1 (also known as kappa-theraphototoxin Hm1a or HmTx1) is a neurotoxin produced by the venom glands of Heteroscodra maculata (Togo starburst tarantula) ^[1] that shifts the activation threshold of voltage-gated potassium channels to more positive potentials.^[2]

Sources

Heteroscodratoxin-1 can be obtained from venom glands of Heteroscodra maculata (Togo starburst tarantula or Togo starburst baboon spider).^[2]

Chemistry

Heteroscodratoxin-1 is a basic protein (isoelectric point of 7.7) composed of 35 amino acids with a carboxylated C-terminus. Its sequence shows strong similarity with other taruntala toxins such as Scodratoxin, Hanatoxin and SGTx1. Structurally the protein belongs to the huwentoxin-1 family of inhibitory spider peptides based on its knottin backbone that consists of three crossing disulfide bridges (Cys1-Cys4/Cys2-Cys5/Cys3-Cys6).^[2]

Target

Heteroscodratoxin-1 inhibits subtypes of both delayed rectifier (K_V2.1 and K_V2.2) and A-type rapidly inactivating (K_V4.1, K_V4.2 and K_V4.3) voltage-gated potassium channels. At a concentration of 100-300 nM, in transfected COS cells it blocks 23% of K_V2.1, 19% of K_V2.2, 50% of K_V4.1, 39% of K_V4.2, and 43% of K_V4.3 conductance at a potential of 0 mV. No significant effect on other A-type rapidly inactivating (K_V1.4 and K_V3.4) or delayed rectifier potassium channels (K_V1.1, K_V1.2, K_V1.3, K_V1.5, K_V1.6, K_V1.2/ K_V1.5, or K_VLQT1), or on sodium and calcium channels has been observed.^[2]

Mode of action

It is thought that heteroscodratoxin-1 modifies gating of specific potassium channels by shifting the activation threshold to more positive values. As a result larger depolarizations are needed to open channels. The mechanism underlying this modification has been largely elucidated using molecular docking simulation for the K_V2.1 potassium channel which is highly expressed in mammalian neurons and interacts strongly with heteroscodratoxin-1. In this model the C-terminal residue of the K_V2.1 S3-segment (S3_C) serves as a binding site for Hmtx-1 forming both hydrophobic and hydrophilic bonds. Interaction between the toxin and the potassium channel induces a helical movement of S3_C resulting in limited spatial freedom of the S4-segment which is responsible for channel gating.^[3]

Toxicity

Information on toxic effects of Heteroscodratoxin-1 in humans is not available. In mice, however, it has been found that intracerebroventricular injection of 500 pmol HmTx1 induces convulsions, spasms, tremors and death within 1 hour. At 100 pmol, a less severe response develops, although death still occurs after 2 hours.^[2]

References

• "Kappa-theraphotoxin-Hm1a - Heteroscodra maculata (Togo starburst tarantula)". Uniprot.org. 2011-09-21. Retrieved 2011-10-08. 
• Escoubas, Pierre (2002). "Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies". Molecular Pharmacology. 
• Shiau, Yu-Shuan (2003). "Structural Basis of Binding and Inhibition of Novel Tarantula Toxins in Mammalian Voltage-Dependent Potassium Channels". Chemical research in toxicology. 16 (10): 1217–25. doi:10.1021/tx0341097. PMID 14565763. 

External links

• Heteroscodratoxin-1 from the Uniprot website
• Toxin card for Heteroscodratoxin-1 from the Toxin, Toxin-target database website