Detection of Rap1A as a yessotoxin binding protein from blood cell membranes

Ujihara, Satoru; Oishi, Tohru; Mouri, Ryota; Tamate, Rie; Konoki, Keiichi; Matsumori, Nobuaki; Murata, Michio; Oshima, Yasukatsu; Sugiyama, Naoyuki; Tomita, Masaru; Ishihama, Yasushi

doi:10.1016/j.bmcl.2010.09.080

Cited by 12 publications

(5 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ladder-shaped polyether toxins (e.g., maitotoxin and yessotoxin) have been proposed to target transmembrane proteins within the lipid bilayer (Murata et al, 2008). Their unique structure, in which the spacing of the ether-oxygens closely matches the pitch of -helices of transmembrane proteins, enables multiple interactions involving hydrogen bonding and/or hydrophobic interactions (Murata et al, 2008;Ujihara et al, 2008Ujihara et al, , 2010Torikai et al, 2008). Hence, its amphipathic nature might allow gambierol to modulate Kv channels through the lipid bilayer, where the closed move their VSD up to the activated state upon strong depolarizations, but cannot pass the concerted step leading to channel opening as long as gambierol remained bound.…”

Section: Discussionmentioning

confidence: 99%

The ladder-shaped polyether toxin gambierol anchors the gating machinery of Kv3.1 channels in the resting state

Kopljar

Labro

Block

et al. 2013

Journal of General Physiology

View full text Add to dashboard Cite

Voltage-gated potassium (Kv) and sodium (Nav) channels are key determinants of cellular excitability and serve as targets of neurotoxins. Most marine ciguatoxins potentiate Nav channels and cause ciguatera seafood poisoning. Several ciguatoxins have also been shown to affect Kv channels, and we showed previously that the ladder-shaped polyether toxin gambierol is a potent Kv channel inhibitor. Most likely, gambierol acts via a lipid-exposed binding site, located outside the K+ permeation pathway. However, the mechanism by which gambierol inhibits Kv channels remained unknown. Using gating and ionic current analysis to investigate how gambierol affected S6 gate opening and voltage-sensing domain (VSD) movements, we show that the resting (closed) channel conformation forms the high-affinity state for gambierol. The voltage dependence of activation was shifted by >120 mV in the depolarizing direction, precluding channel opening in the physiological voltage range. The (early) transitions between the resting and the open state were monitored with gating currents, and provided evidence that strong depolarizations allowed VSD movement up to the activated-not-open state. However, for transition to the fully open (ion-conducting) state, the toxin first needed to dissociate. These dissociation kinetics were markedly accelerated in the activated-not-open state, presumably because this state displayed a much lower affinity for gambierol. A tetrameric concatemer with only one high-affinity binding site still displayed high toxin sensitivity, suggesting that interaction with a single binding site prevented the concerted step required for channel opening. We propose a mechanism whereby gambierol anchors the channel’s gating machinery in the resting state, requiring more work from the VSD to open the channel. This mechanism is quite different from the action of classical gating modifier peptides (e.g., hanatoxin). Therefore, polyether toxins open new opportunities in structure–function relationship studies in Kv channels and in drug design to modulate channel function.

show abstract

Section: Discussionmentioning

confidence: 99%

The ladder-shaped polyether toxin gambierol anchors the gating machinery of Kv3.1 channels in the resting state

Kopljar

Labro

Block

et al. 2013

Journal of General Physiology

View full text Add to dashboard Cite

show abstract

“…14 Although PDE is reported to be one of the target proteins of YTX, we found that the Ras superfamily of proteins binds to YTX. 15 A number of synthetic studies of YTX and adriatoxin have been reported by Nakata, 16 Mori, 17 Kadota,18 and Rainier. 19 However, the total synthesis of YTX has not been achieved yet.…”

Section: Synthetic Study Of Yessotoxin Based On the α Cyano Ether Methodsmentioning

confidence: 98%

Convergent Method via ^|^alpha;-Cyano Ethers: A Powerful Strategy for Synthesizing Ladder-Shaped Polyethers

Oishi

2012

J. Synth. Org. Chem. Jpn.

Self Cite

View full text Add to dashboard Cite

“…The specific molecular target of YTX is generally unclear. However, phosphodiesterases, heterogeneous nuclear ribonucleoproteins (hnRPps), heat shock, and Ras proteins have been reported as YTX targets in human lymphocytes, HepG2 cells, and blood cell membranes (Alfonso et al, 2003 ; Young et al, 2009 ; Ujihara et al, 2010 ). The specific organelle targets appear to be the mitochondria and the ribosome (Bianchi et al, 2004 ; Korsnes et al, 2006a , 2014 ).…”

Section: Yessotoxinmentioning

confidence: 99%

Lifetime Distributions from Tracking Individual BC3H1 Cells Subjected to Yessotoxin

Korsnes

2015

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

This work shows examples of lifetime distributions for individual BC3H1 cells after start of exposure to the marine toxin yessotoxin (YTX) in an experimental dish. The present tracking of many single cells from time-lapse microscopy data demonstrates the complexity in individual cell fate and which can be masked in aggregate properties. This contribution also demonstrates the general practicality of cell tracking. It can serve as a conceptually simple and non-intrusive method for high throughput early analysis of cytotoxic effects to assess early and late time points relevant for further analyzes or to assess for variability and sub-populations of interest. The present examples of lifetime distributions seem partly to reflect different cell death modalities. Differences between cell lifetime distributions derived from populations in different experimental dishes can potentially provide measures of inter-cellular influence. Such outcomes may help to understand tumor-cell resistance to drug therapy and to predict the probability of metastasis.

show abstract

Detection of Rap1A as a yessotoxin binding protein from blood cell membranes

Cited by 12 publications

References 36 publications

The ladder-shaped polyether toxin gambierol anchors the gating machinery of Kv3.1 channels in the resting state

The ladder-shaped polyether toxin gambierol anchors the gating machinery of Kv3.1 channels in the resting state

Convergent Method via ^|^alpha;-Cyano Ethers: A Powerful Strategy for Synthesizing Ladder-Shaped Polyethers

Lifetime Distributions from Tracking Individual BC3H1 Cells Subjected to Yessotoxin

Contact Info

Product

Resources

About