Hanatoxin is a

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...

found in the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of the '' Grammostola spatulata''

tarantula Tarantulas comprise a group of large and often hairy spiders of the family Theraphosidae. , 1,040 species have been identified, with 156 genera. The term "tarantula" is usually used to describe members of the family Theraphosidae, although ...

. The toxin is mostly known for inhibiting the activation of

voltage-gated potassium channels Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...

, most specifically

Kv4.2 Potassium voltage-gated channel subfamily D member 2 is a protein that in humans is encoded by the ''KCND2'' gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase ...

and Kv2.1, by raising its activation threshold.

Sources

Hanatoxin is a

spider toxin 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. A remotely related group of atracotoxins operate by opening sodium channels. ...

from the venom of ''Grammostola spatulata''.

Chemistry

Hanatoxin is the common name for two 4.1

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

protein toxins, HaTx₁ and HaTx₂, which are similar in structure. HaTx is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

consisting of the following 35

amino-acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

: 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. Its amino-acid sequence is homologous to various other toxins, including SGTx1 (76%) and

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 (Ca 2+ channels) in neurons. Grammotoxin is also known as omega-grammotoxin SIA ...

(43%), both of which have similar gating-modification properties as hanatoxin.

Target

Hanatoxin binds to several types of voltage-gated ion channels. While the

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

is the highest for the Kv2.1 and Kv4.2 channels, it has been shown that the toxin may also bind to α_1A voltage-gated Ca²⁺ channels. Hanatoxin binds to the S3-S4 link of K⁺ channel-subunits, specifically the S3b segment, and may bind to multiple subunits in a single ion channel.

Mode of action

Similar to α-

scorpion toxin Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, volt ...

s, 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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

of the S4 segment, restricting movement and, therefore, requiring a higher depolarization for channel-activation.

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

venom causes localized pain, itching and burning and does not seem to have any long-term effects on humans. However, it is possible to have an allergic reaction to the venom, which could cause

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

, 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.

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.

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. One of the most promising therapeutic uses of hanatoxin is treatment of

type-2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...

, by helping the regulation of insulin secretion. While HaTx₁ has successfully been synthesized by fusion in E. coli bacteria, its yield is very low (~1%), limiting its pharmacological use.

References

{{Reflist Ion channel toxins Spider toxins