Structural and functional insights into the inhibition of human voltage-gated sodium channels by μ-conotoxin KIIIA disulfide isomers

Tran, Hue N. T.; McMahon, Kirsten L.; Deuis, Jennifer R.; Vetter, Irina; Schroeder, Christina I.

doi:10.1016/j.jbc.2022.101728

Cited by 15 publications

(19 citation statements)

References 99 publications

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“…CnIIIC was found to be equipotent with KIIIA, whereas a lack of inhibitory potency was observed for the other four µ-conotoxins at the highest concentration tested (1 µM). The results for GIIIA, GIIIB and TIIIA were consistent with the homologous µ-conotoxin GIIIC, previously shown to be inactive at hNa V 1.7 [23]. While the results of SIIIA were expected [24], it is interesting that SIIIA (at 10 nmol, corresponding to 0.7 mg/kg) can produce an analgesic effect in a murine model of inflammatory pain [31].…”

Section: µ-Conotoxinsupporting

confidence: 85%

“…One of the challenges in comparing µ-conotoxin inhibitory potency between different studies is the differences in methods and species (human, mouse, and rat) used. While several µ-conotoxins have been evaluated at hNa V 1.7 channels [4,[23][24][25], only a few studies have directly compared µ-conotoxin inhibitory potency at hNa V 1.7 in the same cell background. Therefore, we expanded our screen to analyse the hNa V 1.7 inhibition of other conotoxins by automated whole-cell patch-clamp electrophysiology.…”

Section: A Limited Number Of µ-Conotoxinsmentioning

confidence: 99%

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µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype NaV1.7

McMahon

Tran

Deuis

et al. 2022

Toxins

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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.

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Section: µ-Conotoxinsupporting

confidence: 85%

Section: A Limited Number Of µ-Conotoxinsmentioning

confidence: 99%

µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype NaV1.7

McMahon

Tran

Deuis

et al. 2022

Toxins

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“…A few of the other approaches and questions that have shared this historical path towards discovery should be noted, albeit in brief. Computational approaches such as docking studies using homology models, or molecular dynamics, have been instrumental in understanding sodium channel function and their interactions with conotoxins [165,242,243]; for reviews see [24,244,245], including prokaryotic sodium channels as part of this effort [246][247][248][249] and extending to examine the roles of toxin residues [250] or disulfide linkage connectivity on µ-conotoxin binding and block of sodium permeance [179,251,252].…”

Section: Discussionmentioning

confidence: 99%

“…The N-terminally extended isomer of KIIIA, KIIIB, was also shown to be a potent inhibitor of Na V 1.2, with significant effects on Na V 1.7 [185]. Certain isomers influencing disulfide connectivity of KIIIA had significant impact on its binding to Na V 1.2, Na V 1.4, and Na V 1.7 [179]. The structural determination of SIIIA and the novel µ-conotoxin SIIIB revealed their sequence diversity, with an alpha helical motif conferring binding affinity for this toxin of equivalent potency on Na V 1.2 and Na V 1.4 [168].…”

Section: Conus Species Sequencementioning

confidence: 98%

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Historical Perspective of the Characterization of Conotoxins Targeting Voltage-Gated Sodium Channels

Groome

2023

Marine Drugs

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Marine toxins have potent actions on diverse sodium ion channels regulated by transmembrane voltage (voltage-gated ion channels) or by neurotransmitters (nicotinic acetylcholine receptor channels). Studies of these toxins have focused on varied aspects of venom peptides ranging from evolutionary relationships of predator and prey, biological actions on excitable tissues, potential application as pharmacological intervention in disease therapy, and as part of multiple experimental approaches towards an understanding of the atomistic characterization of ion channel structure. This review examines the historical perspective of the study of conotoxin peptides active on sodium channels gated by transmembrane voltage, which has led to recent advances in ion channel research made possible with the exploitation of the diversity of these marine toxins.

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Identification of sodium channel toxins from marine cone snails of the subgenera Textilia and Afonsoconus

McMahon,

O’Brien,

Schroeder

et al. 2023

Cell. Mol. Life Sci.

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Voltage-gated sodium (NaV) channels are transmembrane proteins that play a critical role in electrical signaling in the nervous system and other excitable tissues. µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus) that block NaV channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire; therefore, their venoms have yet to be comprehensively interrogated for µ-conotoxins. The goal of this study was to find new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigate their selectivity at human NaV channels. Using RNA-seq of the venom gland of Conus (Textilia) bullatus, we identified 12 µ-conotoxin (or µ-conotoxin-like) sequences. Based on these sequences we designed primers which we used to identify additional µ-conotoxin sequences from DNA extracted from historical specimens of species from Textilia and Afonsoconus. We synthesized six of these µ-conotoxins and tested their activity on human NaV1.1–NaV1.8. Five of the six synthetic peptides were potent blockers of human NaV channels. Of these, two peptides (BuIIIB and BuIIIE) were potent blockers of hNaV1.3. Three of the peptides (BuIIIB, BuIIIE and AdIIIA) had submicromolar activity at hNaV1.7. This study serves as an example of the identification of new peptide toxins from historical DNA and provides new insights into structure–activity relationships of µ-conotoxins with activity at hNaV1.3 and hNaV1.7.

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Structural and functional insights into the inhibition of human voltage-gated sodium channels by μ-conotoxin KIIIA disulfide isomers

Cited by 15 publications

References 99 publications

µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype NaV1.7

µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype NaV1.7

Historical Perspective of the Characterization of Conotoxins Targeting Voltage-Gated Sodium Channels

Identification of sodium channel toxins from marine cone snails of the subgenera Textilia and Afonsoconus

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