Toxin modulators and blockers of hERG K+ channels

Jiménez-Vargas, Juana María; Restano-Cassulini, Rita; Possani, Lourival D.

doi:10.1016/j.toxicon.2012.03.024

Cited by 27 publications

(18 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BeKm-1 discriminates well within the three rat channels, with K D values in the range 1.5 – 757 nM. Contrary to the human channels, the effects on ERG1 and ERG3 are similar, but on ERG2 channel the effect is weaker (Jiménez-Vargas et al, 2012). The HERG channels are associated in the cell cycle and proliferation of several cancers, therefore the use of specific blockers of the channel could inhibit the proliferation of tumor cells.…”

Section: K+-channel Specific Scorpion Toxinsmentioning

confidence: 92%

“…These peptides were found in scorpions of the genus Centruroides, Mesobuthus and Buthus (Zeng et al, 2006; Jiménez-Vargas et al, 2012). The first peptide isolated was ErgTx1 ( C. noxius; Gurrola et al, 1999a), followed by the BeKm-1 ( B. eupeus; Korolkova et al, 2001); other 26 members of this subfamily were Ergtoxin-like peptides isolated from scorpions of the genus Centruroides (Lecchi et al, 2002; Nastainzky et al, 2002; Corona et al, 2002; Coronas et al, 2005; Restano-Cassulini et al, 2008; Jiménez-Vargas et al, 2012) and BmKKx2 (from M. martensii; Zeng et al, 2006). The γ-KTxs were described as mainly targeting hERG channels (Coronas et al, 2002).…”

Section: K+-channel Specific Scorpion Toxinsmentioning

confidence: 99%

See 1 more Smart Citation

Scorpion venom components that affect ion-channels function

Quintero-Hernández

Jiménez-Vargas

Gurrola

et al. 2013

Toxicon

Self Cite

226

168

View full text Add to dashboard Cite

SUMMARY The number and types of venom components that affect ion-channel function are reviewed. These are the most important venom components responsible for human intoxication, deserving medical attention, often requiring the use of specific anti-venoms. Special emphasis is given to peptides that recognize Na+-, K+- and Ca++-channels of excitable cells. Knowledge generated by direct isolation of peptides from venom and components deduced from cloned genes, whose amino acid sequences are deposited into databanks are now adays in the order of 1.5 thousands, out of an estimate biodiversity closed to 300,000. Here the diversity of components is briefly reviewed with mention to specific references. Structural characteristic are discussed with examples taken from published work. The principal mechanisms of action of the three different types of peptides are also reviewed. Na+-channel specific venom components usually are modifier of the open and closing kinetic mechanisms of the ion-channels, whereas peptides affecting K+-channels are normally pore blocking agents. The Ryanodine Ca++-channel specific peptides are known for causing sub-conducting stages of the channels conductance and some were shown to be able to internalize penetrating inside the muscle cells.

show abstract

Section: K+-channel Specific Scorpion Toxinsmentioning

confidence: 92%

Section: K+-channel Specific Scorpion Toxinsmentioning

confidence: 99%

Scorpion venom components that affect ion-channels function

Quintero-Hernández

Jiménez-Vargas

Gurrola

et al. 2013

Toxicon

Self Cite

226

168

View full text Add to dashboard Cite

show abstract

“…Single channel measurements in eukaryotic cellular systems, (Zhou et al 1998) cardiac myocytes, (Liu et al 2004) and Xenopus oocytes (Zou et al 1997) show a 10-14 pS conductance. A number of compounds have been found as hERG activators (Asayama et al 2013) or inhibitors, (Zhou et al 1998;Huang et al 2010;Jiménez-Vargas et al 2012;Long et al 2013) including E-4031, astemizole, and dofetilide as well as quaternary ammonium compounds. Measurement of drug potency and determination of IC 50 values is important for drug discovery and also safety screening, (Hancox et al 2008) due to hERG's involvement in QT prolongation.…”

Section: Introductionmentioning

confidence: 99%

Single channel and ensemble hERG conductance measured in droplet bilayers

Vijayvergiya

Acharya

Poulos³

et al. 2015

Biomed Microdevices

View full text Add to dashboard Cite

The human ether-a-go-go related gene (hERG) encodes the potassium channel Kv11.1, which plays a key role in the cardiac action potential and has been implicated in cardiac disorders as well as a number of off-target pharmaceutical interactions. The electrophysiology of this channel has been predominantly studied using patch clamp, but lipid bilayers have the potential to offer some advantages, including apparatus simplicity, ease of use, and the ability to control the membrane and solution compositions. We made membrane preparations from hERG-expressing cells and measured them using droplet bilayers, allowing measurement of channel ensemble currents and 13.5 pS single channel currents. These currents were ion selective and were blockable by E-4031 and dofetilide in a dose-dependent manner, allowing determination of IC50 values of 17 nM and 9.65 μM for E-4031 and dofetilide, respectively. We also observed time- and voltage- dependent currents following step changes in applied potential that were similar to previously reported patch clamp measurements.

show abstract

“…A variety of natural toxins are known to target hERG channels, 32 including but not limited to scorpion venoms, 33 spider venoms, 34 sea anemone toxins, 35 and the algal toxins ciguatoxin, 36 and gambierol. 37 The aim of the current study was to examine the effects of AZAs on human ERG channels, providing the first mechanistic description of this interaction.…”

Section: Introductionmentioning

confidence: 99%

Marine Algal Toxin Azaspiracid Is an Open-State Blocker of hERG Potassium Channels

Twiner

Doucette

Rasky

et al. 2012

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Azaspiracids (AZA) are polyether marine dinoflagellate toxins that accumulate in shellfish and represent an emerging human health risk. Although human exposure is primarily manifested by severe and protracted diarrhea, this toxin class has been shown to be highly cytotoxic, a teratogen to developing fish, and a possible carcinogen in mice. Until now, AZA's molecular target(s) has not yet been determined. Using three independent methods (voltage clamp, channel binding assay, and thallium flux assay), we have for the first time demonstrated that AZA1, AZA2, and AZA3 each bind to and block the hERG (human ether-à-go-go related gene) potassium channel heterologously expressed in HEK-293 mammalian cells. Inhibition of K+ current for each AZA analogue was concentration-dependent (IC50 value range: 0.64 - 0.84 μM). The mechanism of hERG channel inhibition by AZA1 was investigated further in Xenopus oocytes where it was shown to be an open state-dependent blocker and, using mutant channels, to interact with F656 but not with Y652 within the S6 transmembrane domain that forms the channel's central pore. AZA1, AZA2, and AZA3 were each shown to inhibit [3H]dofetilide binding to the hERG channel and thallium ion flux through the channel (IC50 value range: 2.1 – 6.6 μM). AZA1 did not block K+ current of the closely related EAG1 channel. Collectively, these data suggest that the AZAs physically block the K+ conductance pathway of hERG1 channels by occluding the cytoplasmic mouth of the open pore. Although the concentrations necessary to block hERG channels are relatively high, AZA-induced blockage may prove to contribute to the toxicological properties of the AZAs.

show abstract

Toxin modulators and blockers of hERG K+ channels

Cited by 27 publications

References 92 publications

Scorpion venom components that affect ion-channels function

Scorpion venom components that affect ion-channels function

Single channel and ensemble hERG conductance measured in droplet bilayers

Marine Algal Toxin Azaspiracid Is an Open-State Blocker of hERG Potassium Channels

Contact Info

Product

Resources

About