Tarantula toxins interacting with voltage sensors in potassium channels

Abstract

Voltage-activated ion channels open and close in response to changes in membrane voltage, a process that is crucial for electrical signaling in the nervous system. The venom from many poisonous creatures contains a diverse array of small protein toxins that bind to voltage-activated channels and modify the gating mechanism. Hanatoxin and a growing number of related tarantula toxins have been shown to inhibit activation of voltage-activated potassium (K(v)) channels by interacting with their voltage-sensing domains. This review summarizes our current understanding of the mechanism by which these toxins alter gating, the location of the toxin receptor within K(v) channels and the disposition of this receptor with respect to the lipid membrane. The conservation of tarantula toxin receptors among voltage-activated ion channels will also be discussed.

Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain II Voltage Sensor in the Closed Configuration

“…Several tarantula toxins have been identified that inhibit activation of potassium channels by interacting with S3-S4 linkers (31). Potassium channels can be formed by four identical subunits, and although it seems that multiple toxin molecules can simultaneously bind a potassium channel it also seems that binding of only one toxin molecule per potassium channel is needed to produce channel inhibition (31). Our mutagenesis data indicate that binding of one HWTX-IV molecule per channel is sufficient and necessary for VGSC inhibition.…”

“…ProTx-II does not apparently target other known receptor sites, suggesting the existence of a novel toxin binding site coupled to activation. Several tarantula toxins have been identified that inhibit activation of potassium channels by interacting with S3-S4 linkers (31). Potassium channels can be formed by four identical subunits, and although it seems that multiple toxin molecules can simultaneously bind a potassium channel it also seems that binding of only one toxin molecule per potassium channel is needed to produce channel inhibition (31).…”

Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells

“…Spider VSTs have an "inhibitory cystine knot" fold that is stabilized by disulfide bridges. These structurally similar VSTs act upon Ca 2+ , Na + , and K + channels, some with remarkable specificity for particular channel subtypes (22). VSTs are water-soluble peptides that partition into the outer leaflet of the plasma membrane, where they bind to the extracellular edge of VGIC transmembrane segments that form voltage sensors (21,(23)(24)(25)(26).…”

Structural Determinants of the High Affinity Extracellular Zinc Binding Site on Cav3.2 T-type Calcium Channels

“…The ability of hanatoxin to reduce channel activity and shift channel gating was also localized to the S3-S4 loop of K v 2.1 channels (21). Hanatoxin interaction with the S3-S4 loop of the K v 2.1 channel was thought to stabilize a closed state of the channel thereby reducing channel opening (21,22). We previously proposed that the mechanism of nickel inhibition of Ca v 3.2 channel activity may be similar to the mechanism of hanatoxin inhibition (15).…”