Imperatoxin i

Imperatoxin I (IpTxi) is a peptide toxin which inhibits the Ryanodine receptor (RyR) by making a lipid product.

Source

The toxin comes from the venom of the African scorpion "Pandinus imperator".

[cite journal |author=Valdivia HH, Kirby MS, Lederer Coronado R
title= Scorpion toxins targeted against the sarcoplasmic reticulum Ca(2+)-release channel of skeletal and cardiac muscle. |journal=Proc. Natl. Acad. Sci. |volume=89 |pages=12185-12189|year=1992 |pmid= 1334561 |url=http://www.ncbi.nlm.nih.gov/pubmed/ 1334561

]

Chemistry

The structure of IpTxi:
- two polypeptides. A large subunit of 104 amino acids and a smaller one of 27 amino acids.
- Subunits are linked by a disulfide bond.
- Phospholipase A2 (PLA2) activity on the large subunit

Molecular weight

The molecular weight of the toxin is 15 kDa.

Target

IpTxi acts on the Ryanodine receptors (RyR), these are intracellular Ca2+ release channels mainly known for their role in regulating Ca2+ release from the sarcoplasmatic reticulum of striated muscles [cite journal |author=Franzini/Armstrong C, Protasi F |title= Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions. |journal=Physiol. Rev. |volume=77 |issue=3 |pages=699-729 |year=1997 |pmid= 9234963 |url=http://www.ncbi.nlm.nih.gov/pubmed/9234963

] .

Mode of action

When an action potential reaches the muscle, RyR channels open and Ca2+ will come available in the cell to induce contraction.
The presence of Ca2+ induces the large subunit of IpTxi to hydrolyze the Sn2 fatty acyl bond from the membrane of the sarcoplasmatic reticulum. This process is executed by PLA2 activity. The freed fatty acids bind to the RyR itself or to a closely associated protein linked to gating. Binding of the RyR induce blocking of the channel. When the concentration of free fatty acids is low there will be an incomplete block of RyR, higher concentrations will give an complete block. [cite journal |author=Zamudio FZ, Conde R, Arévalo C, Becerril B, Martin BM, Valdivia HH, Possani LD |title=The mechanism of inhibition of ryanodine receptor channels by imperatoxin I, a heterodimeric protein from the scorpion Pandinus imperator. |journal=J Biol Chem. |volume=272 |issue=18 |pages=11886-94 |year=1997 |pmid= 9115249 |url=http://www.ncbi.nlm.nih.gov/pubmed/9115249

]

Treatment

Treatment with p-bromophenacybromide (pBPB ) decreases the PLA2 activity which reduces IpTxi’s capacity to block the RyR. [cite journal |author=Zamudio FZ, Conde R, Arévalo C, Becerril B, Martin BM, Valdivia HH, Possani LD |title=The mechanism of inhibition of ryanodine receptor channels by imperatoxin I, a heterodimeric protein from the scorpion Pandinus imperator. |journal=J Biol Chem. |volume=272 |issue=18 |pages=11886-94 |year=1997 |pmid= 9115249 |url=http://www.ncbi.nlm.nih.gov/pubmed/9115249

]

Therapeutic use

IpTxi works also on the RyR channels of the heart muscles, it could be used as a drugs against arrhythmia. This has not been proved by studies yet, so it has to be studied "in vivo" first. [cite journal |author=Santonastasi M, Wherens HT,
title= Ryanodine receptors as pharmacological targets for heart disease. |journal= Acta pharmacologica Sinca. |volume=7 |pages=937-944|year=2007 |pmid= 17588328 |url=http://www.ncbi.nlm.nih.gov/pubmed/17588328

]

References

reflist