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Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Michael Adler, Ajay K. Singh, Nizamettin Gul, Frank J. Lebeda
Additional combinations of K+ channel blockers against BoNT intoxication were investigated by Lowery et al. (2013) using three neurotoxic peptides derived from scorpion venom that are selective and highly potent K+ channel blockers. The inhibitors were margatoxin (Kv1.3-selective), iberiotoxin (KCa1.1-selective), and charybdotoxin (potent non-selective antagonist of Kv1.1–1.3, 1.6; KCa1.1; and KCa3.1 channels). In addition to being potent and selective, these toxins act from the extracellular membrane surface, thereby reducing the likelihood of CNS toxicity (Bergeron and Bingham, 2012).
The voltage-gated K+ channel Kv1.3 modulates platelet motility and α2β1 integrin-dependent adhesion to collagen
Published in Platelets, 2022
Joy R Wright, Sarah Jones, Sasikumar Parvathy, Leonard K Kaczmarek, Ian Forsythe, Richard W Farndale, Jonathan M Gibbins, Martyn P Mahaut-Smith
The experiments reported here raise a number of key questions that we have not been able to investigate due to the impact of the COVID-19 pandemic on our laboratories. This challenge has been recognized by Journal editorial policies [56]andwe report here the completed aspects to the work which highlight the need for additional studies. Future experiments should investigate the mechanism responsible for enhanced ADP-evoked aggregation and secretion in Kv1.3−/- platelets and whether responses to other G-protein-coupled receptor agonists are affected. We also propose a pharmacological approach using blockers such as margatoxin and Pap-1. A key area to investigate is the mechanism by which Kv1.3 modulates integrin function and motility; particularly important questions are whether channel opening is required and whether there is an involvement of the K+ channel regulatory proteins identified in our platelet ion channel transcriptome study[12]. The effect of Kv1.3 deletion on interactions with other adhesive substrates is worthwhile investigating, which would benefit from more advanced imaging approaches. Given the enhanced platelet lifespan and increased platelet number in Kv1.3-deficient mice, additional studies should also investigate the presence of mitoKv1.3 and its potential role in the platelet.
A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3
Published in mAbs, 2018
Janna Bednenko, Rian Harriman, Lore Mariën, Hai M. Nguyen, Alka Agrawal, Ashot Papoyan, Yelena Bisharyan, Joanna Cardarelli, Donna Cassidy-Hanley, Ted Clark, Darlene Pedersen, Yasmina Abdiche, William Harriman, Bas van der Woning, Hans de Haard, Ellen Collarini, Heike Wulff, Paul Colussi
Evidence that the recombinant channel assembles into a tetramer was based on staining of fixed cells with K+ channel peptide toxins. Agitoxin-2 (AgTX-2), Margatoxin (MgTX), and Stichodactyla toxin (ShK) are potent Shaker potassium channel blockers derived from the venom of scorpions (AgTX-2; MgTX), and the sea anemone, Stichodactyla helianthus (ShK).19-21 These peptide inhibitors bind with high-affinity to the outer vestibule of the tetrameric channel, occlude ion conductance through the pore, and have been used extensively for probing K+ channel structure.22-27 Fluorescence microscopy showed that both AgTX-2- and ShK-TAMRA bind Tetrahymena cells expressing Kv1.3, but not wild-type negative control cells (Fig. 1e). At higher magnification, toxins were found to localize at the cell periphery or perinuclear areas enriched in endoplasmic reticulum (ER), suggesting that Kv1.3 assembles into tetramers in the ER before being transported to the cell surface (Fig. 1e; top right panel). To ensure binding of the labeled toxins was specific for Kv1.3, cells were co-incubated with 10-fold saturating amounts of competing non-labeled MgTX or Iberiotoxin (IbTX). Iberiotoxin is a potent blocker of large conductance Ca2+-activated K+ channels derived from Burthus tamulus scorpion venom that does not affect voltage-gated potassium channels such as Kv1.3.28Fig. 1f shows that MgTX, but not IbTX, competes with both AgTX-2- and ShK-TAMRA binding in Kv1.3 expressing cells. These results confirm that Kv1.3 traffics to the Tetrahymena cell surface as a correctly assembled tetramer.
Why do platelets express K+ channels?
Published in Platelets, 2021
Joy R Wright, Martyn P. Mahaut-Smith
Kv1.3 has a threshold for activation of about −60 mV, thus accounting for its ability to set the resting membrane potential in both platelets and megakaryocytes [4,6]. Block of the channel with CTX or margatoxin causes a depolarization of ~25-35 mV from the resting membrane potential of −50 to −60 mV leading to a reduction in Ca2+ entry following stimulation of P2X1 receptors or store-operated Ca2+ channels [4,6]. This effect on Ca2+ influx can be explained by the depolarizing influence of Ca2+ or Na+ influx through agonist-activated cation channels and the fact that Kv1.3 is strongly activated by small depolarizations from the resting membrane potential [4,6].