CmERG1

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The CmERG1 toxin is a peptide composed of 42 amino acids, found in venom from the Colombian scorpion Centruroides margaritatus. It blocks human ether-a-go-go-Related gene (hERG) potassium channels, which are important for cardiac action potential repolarization. [1] [2]

Contents

Source and etymology

CmERG1 (or γ-KTx1.10, due to it being the 10th member of the γ-KTx family) is obtained from the venomous glands of the scorpion C. margaritatus, endemic to the upper and middle area of the Cauca River (Valle del Cauca, Colombia) [3] and the Patía river Valley (Cauca, Colombia). [4] CmERG1 is an acronym composed of the animal species the toxin is derived from, the ion channel type it binds to, and the chronological discovery order.  

Based on international classification, [5] the systemic code of CmERG1 is γ-KTx1.10.

Chemistry

CmERG1 is a 42 residue protein, with a molecular weight of 4792.88 Da and is folded by four disulfide bonds. Its primary sequence is as follows:

DRDSCVDKSRCAKYGYFQECTDCCKKYGHNGGTCMFFKCKCA.

CmERG1 is part of the γ-KTx family, which binds selectively to hERG potassium channels.

CmERG1 has a 90.5% homology with CnERG1 (or γ-KTx1.1) and except for F17 (which is a Y in CnERG1), shares the same residues involved in hERG1 binding, namely K13, Y14, Q18, Q21 M35 and F37 [1] [6] [7] However, despite its similarities to other γ-KTxs, CmERG1 almost completely blocks the channel pore at higher concentrations, suggesting that it exhibits a more stable pore-blocking action on hERG1 potassium channels than other members of the γ-KTx family; which typically still allow approximately 10% of the current to pass at saturating concentrations. [1]

Target

Toxins within the γ-KTx family bind selectively to ERG potassium channels, however, CmERG1 has been suggested to have a higher affinity for hERG potassium channels due to its 100% elimination of ionic channel current. [1]

Moreover, the blocking of potassium channels by CmERG1 is fast and reversible, resembling the action of CnERG1 on hERG1. CmERG1 has been found to have an IC50 value of 3.4 ± 0.2 nM and a slope of 1.1 ± 0.05, by fitting dose-response curves with toxin concentrations ranging from 1nM to 1 μM.

Mode of action

Although the difference in the mode of action of CmERG1 from other γ-KTx toxins has not yet been demonstrated beyond speculations from potential changes in binding affinities, the general action of γ-KTx toxins can be viewed under Ergtoxin.

Toxicity

Although the toxicity of purified CmERG1 has not been reported, the toxicity of the venom of C. margaritatus has been investigated, of which CmERG1 is a key, distinguishable ion channel toxin. The toxicity was shown to be different for two populations of the species dependent on their geographical location, and the LD50 was demonstrated to be 42.83 and 59.9 mg/kg for the populations located in the Patia Valley and the Cauca Valley, respectively. [8] [4]

Therapeutic use

It has been shown that hERG channels play a role in cell proliferation, survival and progression in cancers of various organs. [9] Efforts have been made to investigate whether γ-KTxs could be a target for the treatment of ovarian cancer, by inhibiting the proliferation of cells and therefore the development of cancer. [10] Nonetheless, the precise mechanisms underlying hERG channel proliferation in ovarian cancer cells are not yet confirmed.

Related Research Articles

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<span class="mw-page-title-main">Margatoxin</span>

Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of Centruroides margaritatus, also known as the Central American Bark Scorpion. Margatoxin was first discovered in 1993. It was purified from scorpion venom and its amino acid sequence was determined.

<span class="mw-page-title-main">Cobatoxin</span> Chemical compound

Cobatoxin is a toxin present in the venom of the scorpion Centruroides noxius. It blocks two potassium channel subtypes; voltage-gated and calcium-activated channels.

BmTx3 is a neurotoxin, which is a component of the venom of the scorpion Buthus Martensi Karsch. It blocks A-type potassium channels in the central nervous system and hERG-channels in the heart.

Centruroides baergi is a species of scorpion in the family Buthidae. They are commonly found in highlands and are almost exclusively found in the states of Oaxaca and southern Puebla, Mexico. C. baergi is the most abundant scorpion of the genus in the state of Oaxaca, making up a third of Centruroides reported between 2008 and 2014.

Anuroctoxin is a peptide from the venom of the Mexican scorpion Anuroctonus phaiodactylus. This neurotoxin belongs to the alpha family of potassium channel acting peptides. It is a high-affinity blocker of Kv1.3 channels.

Butantoxin (BuTX) is a compound of the venom of three Brazilian and an Argentinean scorpion species of the genus Tityus. Butantoxin reversibly blocks the voltage-gated K+ channels Shaker B and Kv1.2, and the Ca2+-activated K+ channelsKCa 1.1 and KCa 3.1.

Ergtoxin is a toxin from the venom of the Mexican scorpion Centruroides noxius. This toxin targets hERG potassium channels.

<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

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AmmTX3, produced by Androctonus mauretanicus, is a scorpion toxin of the α-KTX15 subfamily. The toxin is known for its ability to act as a specific Kv4 channel blocker, and thereby reducing the A-type potassium current through this channel.

<span class="mw-page-title-main">Noxiustoxin</span> Toxin from the venom of the scorpion Centruroides noxius

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<span class="mw-page-title-main">ImKTx88</span>

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MeuKTX, which belongs to the α-KTx toxin subfamily, is a neurotoxin present in the venom of Mesobuthus eupeus. This short-chain peptide blocks potassium channels, such as Kv1.1, Kv1.2 and Kv1.3.

Centruroides noxius is a species of scorpion native to Mexico.

<span class="mw-page-title-main">Tst26</span>

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<span class="mw-page-title-main">OdK2</span>

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Tb1 is a neurotoxin that is naturally found in the venom of the Brazilian scorpion Tityus bahiensis. Presumably by acting on voltage-gated sodium channels, it triggers excessive glutamate release, which can lead to both behavioral and electrographic epileptiform alterations, as well as neuronal injury.

κ-KTx2.5 is a toxin found in the venom of the scorpion, Opisthacanthuscayaporum. The toxin belongs to the κ-KTx family, a channel blocker family that targets voltage-gated potassium channels (Kv) 1.1 and 1.4.

References

  1. 1 2 3 4 Perrin, Mark J.; Subbiah, Rajesh N.; Vandenberg, Jamie I.; Hill, Adam P. (October 2008). "Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction". Progress in Biophysics and Molecular Biology. 98 (2–3): 137–148. doi: 10.1016/j.pbiomolbio.2008.10.006 . ISSN   0079-6107. PMID   19027781.
  2. ↑ Beltrán-Vidal, José; Carcamo-Noriega, Edson; Pastor, Nina; Zamudio-Zuñiga, Fernando; Guerrero-Vargas, Jimmy Alexander; Castaño, Santiago; Possani, Lourival Domingos; Restano-Cassulini, Rita (2021-06-08). "Colombian Scorpion Centruroides margaritatus: Purification and Characterization of a Gamma Potassium Toxin with Full-Block Activity on the hERG1 Channel". Toxins. 13 (6): 407. doi: 10.3390/toxins13060407 . ISSN   2072-6651. PMC   8273696 . PMID   34201318.
  3. ↑ Guerrero-Vargas, Jimmy Alexander; Rodríguez Buitrago, Javier Roberto; Ayerbe, Santiago; Flórez Daza, Eduardo; Beltrán Vidal, José Toribio (2014-12-24), "Scorpionism and Dangerous Species of Colombia", Scorpion Venoms, Dordrecht: Springer Netherlands, pp. 245–272, doi:10.1007/978-94-007-6404-0_22, ISBN   978-94-007-6403-3 , retrieved 2022-10-27
  4. 1 2 Marinkelle, C. J.; Stahnke, H. L. (1965-06-20). "Toxicological And Clinical Studies On Centruroides Margaritatus (Gervais), A Common Scorpion In Western Colombia.1". Journal of Medical Entomology. 2 (2): 197–199. doi: 10.1093/jmedent/2.2.197 . ISSN   1938-2928. PMID   5318265.
  5. ↑ Tytgat, Jan; Chandy, K.George; Garcia, Maria L; Gutman, George A; Martin-Eauclaire, Marie-France; van der Walt, Jurg J; Possani, Lourival D (November 1999). "A unified nomenclature for short-chain peptides isolated from scorpion venoms: α-KTx molecular subfamilies". Trends in Pharmacological Sciences. 20 (11): 444–447. doi:10.1016/s0165-6147(99)01398-x. ISSN   0165-6147. PMID   10542442.
  6. ↑ Jimenez-Vargas, J.M.; Restano-Cassulini, R.; Possani, L.D. (May 2012). "Interacting sites of scorpion toxin ErgTx1 with hERG1 K+ channels". Toxicon. 59 (6): 633–641. doi:10.1016/j.toxicon.2012.02.001. ISSN   0041-0101. PMID   22366117.
  7. ↑ Wang, Xueli; Jimenez-Vargas, Juana Maria; Xu, Chenqi; Possani, Lourival D.; Zhu, Shunyi (December 2012). "Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K+ channel toxins". Biochemical and Biophysical Research Communications. 429 (1–2): 111–116. doi: 10.1016/j.bbrc.2012.10.065 . ISSN   0006-291X. PMID   23103547.
  8. ↑ "Venom, Scorpion, Centruroides Limpidus Limpidus Compound 93413-69-5", Sax's Dangerous Properties of Industrial Materials, Hoboken, NJ, USA: John Wiley & Sons, Inc., pp. 1–2, 2012-10-15, doi:10.1002/0471701343.sdp51101, ISBN   978-0471701347 , retrieved 2022-10-27
  9. ↑ Asher, Viren; Sowter, Heidi; Shaw, Robert; Bali, Anish; Khan, Raheela (December 2010). "Eag and HERG potassium channels as novel therapeutic targets in cancer". World Journal of Surgical Oncology. 8 (1): 113. doi: 10.1186/1477-7819-8-113 . ISSN   1477-7819. PMC   3022597 . PMID   21190577.
  10. ↑ Asher, Viren; Warren, Averil; Shaw, Robert; Sowter, Heidi; Bali, Anish; Khan, Raheela (2011). "The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line". Cancer Cell International. 11 (1): 6. doi: 10.1186/1475-2867-11-6 . ISSN   1475-2867. PMC   3063814 . PMID   21392380.
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