15 results on '"McMahon, Kirsten L."'
Search Results
2. Identification of sodium channel toxins from marine cone snails of the subgenera Textilia and Afonsoconus
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McMahon, Kirsten L., O’Brien, Henrik, Schroeder, Christina I., Deuis, Jennifer R., Venkatachalam, Dhananjeyan, Huang, Di, Green, Brad R., Bandyopadhyay, Pradip K., Li, Qing, Yandell, Mark, Safavi-Hemami, Helena, Olivera, Baldomero M., Vetter, Irina, and Robinson, Samuel D.
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- 2023
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3. Voltage-Gated Sodium Channel Inhibition by µ-Conotoxins.
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McMahon, Kirsten L., Vetter, Irina, and Schroeder, Christina I.
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SODIUM channels , *CONOTOXINS , *STRUCTURE-activity relationships , *PEPTIDES , *PROMISCUITY , *INDIUM gallium zinc oxide - Abstract
µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (NaV) channels, which have been identified as pharmacological probes and putative leads for analgesic development. A limiting factor in their therapeutic development has been their promiscuity for different NaV channel subtypes, which can lead to undesirable side-effects. This review will focus on four areas of µ-conotoxin research: (1) mapping the interactions of µ-conotoxins with different NaV channel subtypes, (2) µ-conotoxin structure–activity relationship studies, (3) observed species selectivity of µ-conotoxins and (4) the effects of µ-conotoxin disulfide connectivity on activity. Our aim is to provide a clear overview of the current status of µ-conotoxin research. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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4. Changes in Potency and Subtype Selectivity of Bivalent NaV Toxins are Knot-Specific.
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Tran, Poanna, Tran, Hue N. T., McMahon, Kirsten L., Deuis, Jennifer R., Ragnarsson, Lotten, Norman, Alexander, Sharpe, Simon J., Payne, Richard J., Vetter, Irina, and Schroeder, Christina I.
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- 2023
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5. Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function.
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Jami, Sina, Deuis, Jennifer R., Klasfauseweh, Tabea, Cheng, Xiaoyang, Kurdyukov, Sergey, Chung, Felicity, Okorokov, Andrei L., Li, Shengnan, Zhang, Jiangtao, Cristofori-Armstrong, Ben, Israel, Mathilde R., Ju, Robert J., Robinson, Samuel D., Zhao, Peng, Ragnarsson, Lotten, Andersson, Åsa, Tran, Poanna, Schendel, Vanessa, McMahon, Kirsten L., and Tran, Hue N. T.
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SODIUM channels ,STINGING nettle ,TOXINS ,MEMBRANE proteins ,PEPTIDES ,SENSORY neurons - Abstract
Voltage-gated sodium (Na
V ) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV 1.7. These findings identify TMEM233 as a previously unknown NaV 1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons. Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV 1.7. [ABSTRACT FROM AUTHOR]- Published
- 2023
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6. µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na V 1.7.
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McMahon, Kirsten L., Tran, Hue N. T., Deuis, Jennifer R., Craik, David J., Vetter, Irina, and Schroeder, Christina I.
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SODIUM channels , *CONOTOXINS , *PEPTIDES , *STRUCTURE-activity relationships , *IN vivo studies , *HUMAN beings - Abstract
µ-Conotoxins are small, potent, peptide voltage-gated sodium (NaV) channel inhibitors characterised by a conserved cysteine framework. Despite promising in vivo studies indicating analgesic potential of these compounds, selectivity towards the therapeutically relevant subtype NaV1.7 has so far been limited. We recently identified a novel µ-conotoxin, SxIIIC, which potently inhibits human NaV1.7 (hNaV1.7). SxIIIC has high sequence homology with other µ-conotoxins, including SmIIIA and KIIIA, yet shows different NaV channel selectivity for mammalian subtypes. Here, we evaluated and compared the inhibitory potency of µ-conotoxins SxIIIC, SmIIIA and KIIIA at hNaV channels by whole-cell patch-clamp electrophysiology and discovered that these three closely related µ-conotoxins display unique selectivity profiles with significant variations in inhibitory potency at hNaV1.7. Analysis of other µ-conotoxins at hNaV1.7 shows that only a limited number are capable of inhibition at this subtype and that differences between the number of residues in loop 3 appear to influence the ability of µ-conotoxins to inhibit hNaV1.7. Through mutagenesis studies, we confirmed that charged residues in this region also affect the selectivity for hNaV1.4. Comparison of µ-conotoxin NMR solution structures identified differences that may contribute to the variance in hNaV1.7 inhibition and validated the role of the loop 1 extension in SxIIIC for improving potency at hNaV1.7, when compared to KIIIA. This work could assist in designing µ-conotoxin derivatives specific for hNaV1.7. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Structural and functional insights into the inhibition of human voltage-gated sodium channels by μ-conotoxin KIIIA disulfide isomers.
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Tran, Hue N. T., McMahon, Kirsten L., Deuis, Jennifer R., Vetter, Irina, and Schroeder, Christina I.
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CONOTOXINS , *DISULFIDES , *SODIUM channels , *ISOMERS , *CONUS , *MOLECULAR structure , *MOLECULAR docking - Abstract
μ-Conotoxins are components of cone snail venom, wellknown for their analgesic activity through potent inhibition of voltage-gated sodium channel (NaV) subtypes, including NaV1.7. These small, disulfide-rich peptides are typically stabilized by three disulfide bonds arranged in a 'native' CysICysIV, CysII-CysV, CysIII-CysVI pattern of disulfide connectivity. However, μ-conotoxin KIIIA, the smallest and most studied μ-conotoxin with inhibitory activity at NaV1.7, forms two distinct disulfide bond isomers during thermodynamic oxidative folding, including Isomer 1 (CysI-CysV, CysII-CysIV, CysIII-CysVI) and Isomer 2 (CysI-CysVI, CysII-CysIV, CysIIICysV), but not the native μ-conotoxin arrangement. To date, there has been no study on the structure and activity of KIIIA comprising the native μ-conotoxin disulfide bond arrangement. Here, we evaluated the synthesis, potency, sodium channel subtype selectivity, and 3D structure of the three isomers of KIIIA. Using a regioselective disulfide bond-forming strategy, we synthetically produced the three μ-conotoxin KIIIA isomers displaying distinct bioactivity and NaV subtype selectivity across human NaV channel subtypes 1.2, 1.4, and 1.7. We show that Isomer 1 inhibits NaV subtypes with a rank order of potency of NaV1.4 > 1.2 > 1.7 and Isomer 2 in the order of NaV1.4≈1.2 > 1.7, while the native isomer inhibited NaV1.4 > 1.7≈1.2. The three KIIIA isomers were further evaluated by NMR solution structure analysis and molecular docking with hNaV1.2. Our study highlights the importance of investigating alternate disulfide isomers, as disulfide connectivity affects not only the overall structure of the peptides but also the potency and subtype selectivity of μ-conotoxins targeting therapeutically relevant NaV subtypes. [ABSTRACT FROM AUTHOR]
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- 2022
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8. The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaV1.8 to Enhance Activation.
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Deuis, Jennifer R., Ragnarsson, Lotten, Robinson, Samuel D., Dekan, Zoltan, Chan, Lerena, Jin, Ai-Hua, Tran, Poanna, McMahon, Kirsten L., Li, Shengnan, Wood, John N., Cox, James J., King, Glenn F., Herzig, Volker, and Vetter, Irina
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SODIUM channels ,PEPTIDES ,VENOM ,TARANTULAS ,CONUS ,BINDING sites - Abstract
Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (Na
V ) channels, however relatively few venom-derived peptides with activity at the mammalian NaV 1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates NaV 1.8. Eo1a is a 37-residue peptide that increases NaV 1.8 peak current (EC50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV50 –20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV50 –15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of NaV 1.1–NaV 1.7, although its activity is most pronounced at NaV 1.8. Investigations into the binding site of Eo1a using NaV 1.7/NaV 1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of NaV 1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at NaV 1.8. [ABSTRACT FROM AUTHOR]- Published
- 2022
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9. Evaluation of Efficient Non-reducing Enzymatic and Chemical Ligation Strategies for Complex Disulfide-Rich Peptides.
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Tran, Hue N. T., Tran, Poanna, Deuis, Jennifer R., McMahon, Kirsten L., Yap, Kuok, Craik, David J., Vetter, Irina, and Schroeder, Christina I.
- Published
- 2021
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10. Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.
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McMahon, Kirsten L., Tay, Bryan, Deuis, Jennifer R., Tanaka, Brian S., Peigneur, Steve, Jin, Ai-Hua, Tytgat, Jan, Waxman, Stephen G., Dib-Hajj, Sulayman D., Vetter, Irina, and Schroeder, Christina I.
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LEECHES , *PAIN perception , *NUCLEAR magnetic resonance spectroscopy , *PATHOLOGY , *CHRONIC pain - Abstract
The role of voltage-gated sodium (Na V) channels in pain perception is indisputable. Of particular interest as targets for the development of pain therapeutics are the tetrodotoxin-resistant isoforms Na V 1.8 and Na V 1.9, based on animal as well as human genetic studies linking these ion channel subtypes to the pathogenesis of pain. However, only a limited number of inhibitors selectively targeting these channels have been reported. HSTX-I is a peptide toxin identified from saliva of the leech Haemadipsa sylvestris. The native 23-residue peptide, stabilised by two disulfide bonds, has been reported to inhibit rat Na V 1.8 and mouse Na V 1.9 with low micromolar activity, and may therefore represent a scaffold for development of novel modulators with activity at human tetrodotoxin-resistant Na V isoforms. We synthetically produced this hydrophobic peptide in high yield using a one-pot oxidation and single step purification and determined the three-dimensional solution structure of HSTX-I using NMR solution spectroscopy. However, in our hands, the synthetic HSTX-I displayed only very modest activity at human Na V 1.8 and Na V 1.9, and lacked analgesic efficacy in a murine model of inflammatory pain. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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11. Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na V Channel Inhibitor.
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McMahon, Kirsten L., Tran, Hue N.T., Deuis, Jennifer R., Lewis, Richard J., Vetter, Irina, and Schroeder, Christina I.
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VOLTAGE-gated ion channels ,CHRONIC pain ,STRUCTURE-activity relationships ,CHEMICAL synthesis ,NEUROLOGICAL disorders ,DRUG development - Abstract
Voltage-gated sodium (Na
V ) channel subtypes, including NaV 1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent NaV channel inhibitors which represent potential drug leads. Of the 22 µ-conotoxins characterised so far, only a small number, including KIIIA and CnIIIC, have shown inhibition against human NaV 1.7. We have recently identified a novel µ-conotoxin, SxIIIC, from Conus striolatus. Here we present the isolation of native peptide, chemical synthesis, characterisation of human NaV channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique NaV channel selectivity profile (1.4 > 1.3 > 1.1 ≈ 1.6 ≈ 1.7 > 1.2 >> 1.5 ≈ 1.8) when compared to other µ-conotoxins and represents one of the most potent human NaV 1.7 putative pore blockers (IC50 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic α-helix seen in other µ-conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for NaV channel pore blocker selectivity and subsequently important for chronic pain drug development. [ABSTRACT FROM AUTHOR]- Published
- 2020
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12. Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7.
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Agwa, Akello J., Tran, Poanna, Mueller, Alexander, Tran, Hue N. T., Deuis, Jennifer R., Israel, Mathilde R., McMahon, Kirsten L., Craik, David J., Vetter, Irina, and Schroeder, Christina I.
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BILAYER lipid membranes , *SODIUM channels , *VOLTAGE-gated ion channels , *MEMBRANE lipids , *HYDROPHOBIC surfaces , *TOXINS - Abstract
Huwentoxin-IV (HwTx-IV) is a gating modifier peptide toxin from spiders that has weak affinity for the lipid bilayer. As some gating modifier toxins have affinity for model lipid bilayers, a tripartite relationship among gating modifier toxins, voltage-gated ion channels, and the lipid membrane surrounding the channels has been proposed. We previously designed an HwTx-IV analogue (gHwTx-IV) with reduced negative charge and increased hydrophobic surface profile, which displays increased lipid bilayer affinity and in vitro activity at the voltage-gated sodium channel subtype 1.7 (NaV1.7), a channel targeted in pain management. Here, we show that replacements of the positively-charged residues that contribute to the activity of the peptide can improve gHwTx-IV's potency and selectivity for NaV1.7. Using HwTx- IV, gHwTx-IV, [R26A]gHwTx-IV, [K27A]gHwTx-IV, and [R29A]gHwTx-IV variants, we examined their potency and selectivity at human NaV1.7 and their affinity for the lipid bilayer. [R26A]gHwTx-IV consistently displayed the most improved potency and selectivity for NaV1.7, examined alongside off-target NaVs, compared with HwTx-IV and gHwTx-IV. The lipid affinity of each of the three novel analogues was weaker than that of gHwTx-IV, but stronger than that of HwTx-IV, suggesting a possible relationship between in vitro potency at NaV1.7 and affinity for lipid bilayers. In a murine NaV1.7 engagement model, [R26A]gHwTx-IV exhibited an efficacy comparable with that of native HwTx-IV. In summary, this study reports the development of an HwTx-IV analogue with improved in vitro selectivity for the pain target NaV1.7 and with an in vivo efficacy similar to that of native HwTx-IV. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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13. Small cyclic sodium channel inhibitors.
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Peigneur, Steve, da Costa Oliveira, Cristina, de Sousa Fonseca, Flávia Cristina, McMahon, Kirsten L., Mueller, Alexander, Cheneval, Olivier, Cristina Nogueira Freitas, Ana, Starobova, Hana, Dimitri Gama Duarte, Igor, Craik, David J., Vetter, Irina, de Lima, Maria Elena, Schroeder, Christina I., and Tytgat, Jan
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SODIUM channels , *CONOTOXINS , *CONUS , *CYCLIC peptides , *MOLECULAR interactions - Abstract
Voltage-gated sodium (Na V) channels play crucial roles in a range of (patho)physiological processes. Much interest has arisen within the pharmaceutical industry to pursue these channels as analgesic targets following overwhelming evidence that Na V channel subtypes Na V 1.7–Na V 1.9 are involved in nociception. More recently, Na V 1.1, Na V 1.3 and Na V 1.6 have also been identified to be involved in pain pathways. Venom-derived disulfide-rich peptide toxins, isolated from spiders and cone snails, have been used extensively as probes to investigate these channels and have attracted much interest as drug leads. However, few peptide-based leads have made it as drugs due to unfavourable physiochemical attributes including poor in vivo pharmacokinetics and limited oral bioavailability. The present work aims to bridge the gap in the development pipeline between drug leads and drug candidates by downsizing these larger venom-derived Na V inhibitors into smaller, more "drug-like" molecules. Here, we use molecular engineering of small cyclic peptides to aid in the determination of what drives subtype selectivity and molecular interactions of these downsized inhibitors across Na V subtypes. We designed a series of small, stable and novel Na V probes displaying Na V subtype selectivity and potency in vitro coupled with potent in vivo analgesic activity, involving yet to be elucidated analgesic pathways in addition to Na V subtype modulation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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14. Changes in Potency and Subtype Selectivity of Bivalent Na V Toxins are Knot-Specific.
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Tran P, Tran HNT, McMahon KL, Deuis JR, Ragnarsson L, Norman A, Sharpe SJ, Payne RJ, Vetter I, and Schroeder CI
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- Humans, Peptides pharmacology
- Abstract
Disulfide-rich peptide toxins have long been studied for their ability to inhibit voltage-gated sodium channel subtype Na
V 1.7, a validated target for the treatment of pain. In this study, we sought to combine the pore blocking activity of conotoxins with the gating modifier activity of spider toxins to design new bivalent inhibitors of NaV 1.7 with improved potency and selectivity. To do this, we created an array of heterodimeric toxins designed to target human NaV 1.7 by ligating a conotoxin to a spider toxin and assessed the potency and selectivity of the resulting bivalent toxins. A series of spider-derived gating modifier toxins (GpTx-1, ProTx-II, gHwTx-IV, JzTx-V, CcoTx-1, and Pn3a) and two pore-blocker μ-conotoxins, SxIIIC and KIIIA, were used for this study. We employed either enzymatic ligation with sortase A for C- to N-terminal ligation or click chemistry for N- to N-terminal ligation. The bivalent peptide resulting from ligation of ProTx-II and SxIIIC (Pro[LPATG6 ]Sx) was shown to be the best combination as native ProTx-II potency at hNaV 1.7 was conserved following ligation. At hNaV 1.4, a synergistic effect between the pore blocker and gating modifier toxin moieties was observed, resulting in altered sodium channel subtype selectivity compared to the parent peptides. Further studies including mutant bivalent peptides and mutant hNaV 1.7 channels suggested that gating modifier toxins have a greater contribution to the potency of the bivalent peptides than pore blockers. This study delineated potential benefits and drawbacks of designing pharmacological hybrid peptides targeting hNaV 1.7.- Published
- 2023
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15. The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel Na V 1.8 to Enhance Activation.
- Author
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Deuis JR, Ragnarsson L, Robinson SD, Dekan Z, Chan L, Jin AH, Tran P, McMahon KL, Li S, Wood JN, Cox JJ, King GF, Herzig V, and Vetter I
- Abstract
Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (Na
V ) channels, however relatively few venom-derived peptides with activity at the mammalian NaV 1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates NaV 1.8. Eo1a is a 37-residue peptide that increases NaV 1.8 peak current (EC50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV50 -20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV50 -15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of NaV 1.1-NaV 1.7, although its activity is most pronounced at NaV 1.8. Investigations into the binding site of Eo1a using NaV 1.7/NaV 1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of NaV 1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at NaV 1.8., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deuis, Ragnarsson, Robinson, Dekan, Chan, Jin, Tran, McMahon, Li, Wood, Cox, King, Herzig and Vetter.)- Published
- 2022
- Full Text
- View/download PDF
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