SHTX is a toxin derived from the sea anemone ''

Stichodactyla haddoni ''Stichodactyla haddoni'', commonly known as Haddon's sea anemone, is a species of sea anemone belonging to the family Stichodactylidae. It is found in the Indo-Pacific area. Description ''S. haddoni'' is characterized by a folded oral disc tha ...

''; there are four different subtypes, SHTX I, II, III and IV. SHTX I, II and III can paralyze crabs by acting on potassium channels, while SHTX IV works on sodium channels, and is lethal to crabs.

Sources

SHTX I, II, III and IV are toxins derived from the sea anemone ''

''.

Chemistry

SHTX I and II consist of 28 amino acids. SHTX I and II have been classified as members of the type IV potassium channel toxin family. The protein sequences of SHTX I and II differ only at amino acid position 6, where the SHTX I protein contains a

hydroxyproline (2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank. Structure and discovery In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gelatin ...

and SHTX II contains a proline. SHTX I contains two

disulfide In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

bridges between Cys-7 and -19 and between Cys-10 and -25., whereas most peptide toxins derived from sea anemones have three disulfide bridges. Because of the extensive homology between SHTX I and II, it is plausible that SHTX II will share the location of the disulfide bridges. SHTX I and II also share homology with Am I, a toxin isolated from the sea anemone ''Antheopsis maculata''. These proteins have the same positions of cysteines in their amino acid sequences, which points towards a comparable structure. Am I is toxic to crabs and is lethal in high doses (LD₅₀ 830 µg/kg), but the target of this toxin is still unknown. The protein SHTX III is a Kunitz-type protease inhibitor, with a length of 62 amino acids. It shows homology to other members of the Kunitz-type protease inhibitor family and the highest similarity is shown with AEPI-I, a toxin derived from the sea anemone ''

Actinia equina The beadlet anemone (''Actinia equina'') is a common sea anemone found on rocky shores around all coasts of the British Isles. Its range extends to the rest of Western Europe and the Mediterranean Sea, and along the Atlantic coast of Africa as f ...

''. SHTX IV is composed of 48 amino acids and is a member of the type 2 sea anemone sodium channel toxin family. The protein shares homology with the other members of this family, especially with the toxin Rp II from the sea anemone ''Radianthus paumotensis''. The amino acid glycine at the C-terminus of the SHTX IV protein is deleted after completing translation. As a result, the mature protein has an amidated lysine at its C-terminus instead of a glycine.

Target

SHTX II acts on voltage-gated potassium channels and was reported to be approximately 50 times less potent than ¹²⁵I-a-

dendrotoxin Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes ('' Dendroaspis'') that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junction ...

to synaptosomal membranes, with an IC₅₀ of 270 nM. The affinity and target of SHTX I has not been assessed yet, however, due to the similarities of SHTX I with SHTX II in both sequence and crab paralyzing activity, it is considered to show the same affinity to potassium channels as SHTX II. SHTX III is known to be a Kunitz-type protease inhibitor and a potassium (

Kv1.2 Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the ''KCNA2'' gene. Function Potassium channels represent the most complex class of voltage-gated ion channels from both functi ...

) channel blocker. It was reported to be approximately 110 times less potent than ¹²⁵I-a-dendrotoxin to synaptosomal membranes, with an IC₅₀ of 650 nM. SHTX IV is a type 2 sea anemone sodium channel toxin and shows 91% sequence overlap with Rp II from the sea anemone ''R. paumotensis''. The affinity of SHTX IV to sodium channels has not been studied yet. However, the affinity of the toxin would most likely depend on the species, the issue and state of innervation it is exposed to.

Mode of action

The modes of action of SHTX I and II are currently unknown. SHTX III has a Kunitz-domain and therefore has a protease inhibitor. In sea anemones, it has been suggested that these protease inhibitors are to protect the toxins injected to the prey and contribute to the paralysis. It also works on potassium (

) channels as a blocker, the precise mechanism is still unknown. SHTX IV is a type 2 sea anemone sodium channel toxin, of which the mode of action has not been studied yet. However, due to the high similarity in its sequence with Rp II it might be possible that it shares the same effect, which is prolonging the inactivation of the sodium channel.

Toxicity

SHTX I, II, III and IV are tested on crabs to reveal their paralytic activity ( ED₅₀) and lethal activity ( LD₅₀). SHTX I, II and III are not lethal to crabs, but they induce paralysis. The values of ED₅₀ are 430 µg/kg for SHTX I and II and 183 µg/kg for SHTX III. However, SHTX IV can be lethal to crabs, with an estimated LD₅₀ of 93 µg/kg. Contact with the sea anemone ''S. haddoni'' can induce an

anaphylactic 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 ...

shock.

Treatment

No specific treatment is available for intoxication with SHTX I, II, III or IV. In addition, it is not known what the specific symptoms of an intoxication with one of these toxins are in humans, since the effects of these toxins have only been tested on crabs.

References

{{Reflist Neurotoxins Ion channel toxins Sea anemone toxins